Thiazolyl urea compounds and methods of uses

ABSTRACT

Selected novel urea compounds are effective for prophylaxis and treatment of diseases, such as cell proliferation or apoptosis mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving stoke, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application Ser. No.10/077,124, filed Feb. 15, 2002, which is a continuation in part of U.S.application Ser. No. 09/930,753, filed Aug. 14, 2001, which claims thebenefit of U.S. provisional application No. 60/225,793, filed Aug. 15,2000, all of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] This invention is in the field of pharmaceutical agents andspecifically relates to compounds, compositions, uses and methods fortreating cell proliferation-related disorders, cell death andapoptosis-related disorders.

BACKGROUND OF THE INVENTION

[0003] Identification of therapeutic agents effective in the treatmentof neoplastic diseases or for the treatment of neurological disorders isthe subject of significant research efforts.

[0004] Protein kinases represent a large family of proteins which play acentral role in the regulation of a wide variety of cellular processesand maintaining control over cellular function. A partial list of suchkinases includes ab1, Akt, bcr-ab1, Blk, Brk, Btk, c-kit, c-met, c-src,CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1,CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2,FGFR3, FGFR4, FGFR5, Fgr, FLK-4, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie,tie2, TRK, Yes, and Zap70. As such, inhibition of kinases has become animportant therapeutic target.

[0005] Cell proliferation is the rapid reproduction of cells, such as bycell division. The cell cycle, which controls proliferation, is itselfcontrolled by a family of serine-threonine kinases called cyclindependent kinases (CDKs). The regulation of CDK activation is complex,and requires the association of the CDK with a member of the cyclinfamily of regulatory subunits. A further level of regulation occursthrough both activating and inactivating phosphorylations of the CDKsubunit. The coordinate activation and inactivation of differentcyclin/CDK complexes is necessary for normal progression through thecell cycle. Both the critical G1-S and G2-M transitions are controlledby the activation of different cyclin/CDK activities. Loss of control ofCDK regulation is a frequent event in hyperproliferative diseases andcancer. (T. Noguchi et al., Am. J. Pathol., 156, 2135-47 (2000)) Assuch, inhibition of CDKs has become an important target in the study ofchemotherapeutics (A. Senderowicz and E. Sausville, J. Nat. Canc.Instit., 92, 376-87 (2000))

[0006] Kinases have also been implicated in diseases and disorders ofthe central nervous system. For example, patients suffering from stroke,Alzheimer's disease or Parkinson's disease would benefit from theinhibition of kinases. Cdk5 has been shown to be involved in Alzheimer'spathology (R. Maccioni, et al., Eur. J. Biochem., 268, 1518-27 (2001))and with neuronal development (G. Paglini and A. Caceres, Eur. J.Biochem., 268, 1528-33 (2001)).

[0007] Protein kinases also control programmed cell death, also known asapoptosis. Apoptosis is a ubiquitous physiological process used toeliminate damaged or unwanted cells in multicellular organisms.Disregulation of apoptosis is believed to be involved in thepathogenesis of many human diseases. The failure of apoptotic cell deathhas been implicated in various cancers, as well as autoimmune disorders.Conversely, increased apoptosis is associated with a variety of diseasesinvolving cell loss such as neurodegenerative disorders and AIDS. Assuch, inhibition of apoptosis has become an important therapeutictarget. Cdk5 has been shown to be involved in apoptosis pathology (A.Catania et al., Neuro-Oncology, 89-98 (April 2001)).

[0008] Substituted heterocyclic compounds are known in the pesticideart. WO00/24735, published May 4, 2000, describes1-pyridyl-1,2,4-triazoles as pesticides. WO00/24739, published May 4,2000, describes substituted 1,2,4-triazoles as pesticides. WO97/01552,published Jan. 16, 1997, describes substituted 1,2,4-triazoles asantifungal agents. DE4204492 describes substituted benzamides aspesticides. WO98/57969, published Dec. 23, 1998, describesheterocyclylpyridines as pesticides. GB2293380, published Mar. 27, 1996,describes the use of heterocyclic compounds as pesticides. U.S. Pat. No.5,693,667, issued Dec. 2, 1997, describes heterocyclic compounds for thetreatment of take-all disease. EP468695 describes fungicide compounds.U.S. Pat. No. 5,294,596, issued Mar. 15, 1994, describes herbicidaltriazolinones. U.S. Pat. No. 5,395,818, issued Mar. 7, 1995, describesherbicidal triazolinones.

[0009] Substituted thiazoles also are known in the pesticide art. U.S.Pat. No. 4,260,765, issued Apr. 7, 1981, describes2-(3-pyridyl)-5-thiazolecarboxamides for the treatment of aphids. U.S.Pat. No. 5,945,380, issued Aug. 31, 1999, describes4-(4-pyridyl)pyrazoles as insecticides. WO89/00568, published Jan. 26,1989, describes nicotine derivatives as fungicides.

[0010] Heterocyclic ureas are known in the pharmaceutical art.WO99/23091, published May 14, 1999, describes heterocyclic compounds asanti-inflammatories. WO99/32455, published Jul. 1, 1999, describesheterocyclic ureas as RAF kinase inhibitors. WO99/32110, published Jul.1, 1999, describes heterocyclic ureas as p38 kinase inhibitors.WO99/32106, published Jul. 1, 1999, describes heterocyclic ureas as RAFkinase inhibitors. WO99/32111, published Jul. 1, 1999, describesheterocyclic ureas as p38 kinase inhibitors. WO99/32436, published Jul.1, 1999, describes urea compounds as inhibitors of RAF kinase.WO99/32463, published Jul. 1, 1999, describes urea compounds thatinhibit p38 kinase. WO98/52558, published Nov. 26, 1998, describes ureacompounds for the inhibition of p38 kinase. WO99/00357, published Jan.7, 1999, describes the use of urea compounds as inhibitors of p38kinase. WO99/58502, published Nov. 18, 1999, describes urea compounds asinhibitors of p38 kinase. U.S. Pat. No. 5,821,245, issued Oct. 13, 1998,describes substituted naphthalene derivatives for treating cell growth.GB patent 1,437,895 describes 2-thiazolyl ureas for the treatment ofulcers. U.S. Pat. No. 5,364,871, issued Nov. 15, 1994 describesthiazoles as anti-ulcer compounds. WO99/21555, published May 6, 1999,describes pyridyl-substituted thiazoles as adenosine A3 receptorantagonists. WO96/23783 describes indole derivatives as 5-HT receptorantagonists. U.S. Pat. No. 5,208,248 describes indazole derivatives as5-HT receptor antagonists. WO99/46244, published Sep. 16, 1999 describesheterocyclic compounds as tyrosine phosphatases. GB patent 2,263,109,published Jul. 14, 1993, describes pyridylthiazoles as PAF-receptorantagonists.

[0011] Thiazole compounds have also been described as inhibitors of CDK.WO00/26203, published May 11, 2000, describes 2-ureidothiazoles asinhibitors of cdk. WO99/65884 describes 2-aminothiazoles as inhibitorsof CDK. WO99/24416 describes 2-aminothiazoles as inhibitors of CDK.

[0012] However, compounds of the current invention have not beendescribed as inhibitors of cell proliferation or apoptosis such as forthe treatment of cancer or stroke.

DESCRIPTION OF THE INVENTION

[0013] A class of compounds useful in treating cell proliferativedisorders, neurological disorders and apoptosis is defined by Formula I

[0014] wherein each of A¹-A⁶ is selected from CH₂, CH, C, O, S, NH andN; wherein A¹-A⁶ together form a ring A selected from

[0015] a) additionally substituted or unsubstituted 5- or 6-memberedheterocyclyl,

[0016] preferably 5- or 6-membered heteroaryl,

[0017] more preferably 5-membered heteroaryl selected from thiazolyl,oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, isoxazolyl, triazolyl andisothiazolyl, and

[0018] 6-membered heteroaryl selected from pyridyl, pyrazinyl,pyrimidinyl and pyridazinyl,

[0019] even more preferably 5-membered heteroaryl selected fromthiazolyl, oxazolyl and imidazolyl, and 6-membered heteroaryl selectedfrom pyridyl, and pyrimidinyl,

[0020] b) additionally substituted or unsubstituted 5- or 6-memberedheteroaryl fused with a phenyl group,

[0021] c) additionally substituted or unsubstituted 5- or 6-memberedcycloalkenyl,

[0022] preferably 5-membered cycloalkenyl,

[0023] more preferably cyclopentadienyl or cyclopentenyl, and

[0024] d) additionally substituted or unsubstituted phenyl,

[0025] wherein A is additionally substituted with one or moresubstituents independently selected from halo, —OR³, —SR³, —CO₂R³,—CO₂NR³R³, —COR³, —NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NR³C(O)R³,cycloalkyl, optionally substituted phenylalkylenyl, optionallysubstituted 5-6 membered heterocyclyl, optionally substitutedheteroarylalkylenyl, optionally substituted phenyl, lower alkyl, cyano,lower hydroxyalkyl, nitro, lower alkenyl, lower alkynyl and lowerhaloalkyl,

[0026] preferably one or more substituents independently selected fromhalo, —OR³, —SR³, —S(O)R³, —CO₂R³, —CO₂NR³R³, —COR³, —NR³R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, C₁-C₂ alkyl, cyano, C₁-C₂ hydroxyalkyl, nitro,C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₁-C₂ haloalkyl,

[0027] more preferably one or more substituents independently selectedfrom fluoro, hydroxy, methoxy, amino and methyl;

[0028] wherein X and Z taken together form a nitrogen containing ringselected from

[0029] unsubstituted 5-6 membered heterocyclyl,

[0030] unsubstituted 5-6 membered heterocyclyl fused with a phenylgroup,

[0031] 5-6 membered heterocyclyl substituted with one or moresubstituents independently selected from R¹, and

[0032] 5-6 membered nitrogen-containing heterocyclyl, fused with aphenyl group, substituted with one or more substituents independentlyselected from R¹,

[0033] preferably a ring selected from substituted or unsubstituted 5-or 6-membered nitrogen-containing heteroaryl, and substituted orunsubstituted 5- or 6-membered nitrogen-containing heteroaryl fused witha phenyl group,

[0034] more preferably substituted or unsubstituted thiazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, isoindolyl, indolyl,indazolyl, purinyl, [1,6]naphthyridinyl,5,6,7,8-tetrahydro[1,6]naphthyridinyl, isoquinolyl and quinolyl,

[0035] even more preferably pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, [1,6]naphthyridinyl and5,6,7,8-tetrahydro[1,6]naphthyridinyl,

[0036] most preferably pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl,

[0037] most preferred pyridyl;

[0038] wherein R¹ is independently selected from H, halo, —OR³, —SR³,—CO₂R³, —CO₂NR³R³, —COR³, —CONR³R³, —NR³R³, —C(S)NR³R³, —SO₂NR³R³,—NR³C(O)OR³, —NR³C(O)R³, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted 4-10 membered heterocyclylalkyl, optionallysubstituted phenyl, optionally substituted phenoxy, lower alkyl, lowercyano, lower alkenyl, lower alkynyl and lower haloalkyl,

[0039] preferably optionally substituted pyrrolidinyl, optionallysubstituted piperazinyl, optionally substituted piperidinyl,morpholinyl, optionally substituted pyridyl,1,4-dioxa-8-aza-spiro[4.5]decyl, optionally substituted phenyl, C₁-C₄alkyl, C₁-C₂ haloalkyl, halo, C₁-C₄-hydroxyalkyl, amino,C₁-C₄-azidoalkyl, C₁-C₄-cyanoalkyl, C₁-C₄-aminoalkyl, hydroxy,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-hydroxyalkylamino-C₁-C₄-alkyl, amino-C₁-C₄-alkoxy-C₁-C₄-alkyl,C₁-C₄-alkylamino-C₁-C₄-alkylamino-C₁-C₄alkyl, (optionally substitutedpyrrolidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, 4-morpholinyl-C₁-C₂-alkyl, (optionallysubstituted imidazolyl)-C₁-C₂-alkyl, phthalimidylethyl, optionallysubstituted azepanyl-C₁-C₂-alkyl,1,4-dioxa-8-aza-spiro(4.5]decyl-C₁-C₂-alkyl, optionally substitutedpyridyloxy, optionally substituted phenoxy, tetrahydrofuryl-O—,(1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substitutedphenoxy-C₁-C₂-alkyl, optionally substituted pyrrolidinyl-C₁-C₄-alkoxy,optionally substituted azetidinyl-C₁-C₄-alkoxy, optionally substitutedpiperidinyl-C₁-C₄-alkoxy, tetrahydrofuryl-C₁-C₄-alkoxy,C₁-C₄-alkylamino-C₁-C₄-alkoxy morpholinyl-C₁-C₄-alkylenylaminocarbonyl,C₁-C₄-alkoxycarbonyl, 5-6-memberedheterocyclyl-C₁-C₄-alkylaminocarbonyl, 5-6-membered N-containingheterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl, 5-6-membered N-containingheterocyclyl-C₁-C₄-alkylamino, aminocarbonyl,C₁-C₃-alkylaminothiocarbonyl, C₁-C₄alkylamino andC₁-C₄-alkylamino-C₁-C₄-alkylamino,

[0040] more preferably 3-(N,N-dimethylamino)-1-pyrrolidinyl,1-methyl-4-piperazinyl, 1-benzyl-4-piperazinyl,1-(2-pyrimidinyl)-4-piperazinyl, 1-(2-pyridyl)-4-piperazinyl,1-ethyl-4-piperazinyl, piperidinyl, morpholinyl, 4-amino-1-piperidinyl,4-(N-hydroxyethylamino)-1-piperidinyl, 4-(N-propylamino)-1-piperidinyl,4-(N-benzylamino)-1-piperidinyl, 4-oxo-piperidinyl,4-(hydroxyimino)-piperidinyl, 4-morpholinyl,1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, amino, azidomethyl,hydroxymethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,fluoro, chloro, bromo, aminoethyl, aminomethyl, cyanomethyl,1-pyrrolidinyl-CH₂—, 2-methoxycarbonyl-1-pyrrolidinyl-CH₂—,2-carboxy-1-pyrrolidinyl-CH₂—, 2-hydroxymethyl-1-pyrrolidinyl-CH₂—,1-piperidinyl-CH₂—, 4-methyl-1-piperidinyl-CH₂—,3-methyl-1-piperidinyl-CH₂—, 2-methyl-1-piperidinyl-CH₂—,3,5-dimethyl-1-piperidinyl-CH₂—, 4-oxo-1-piperidinylCH₂—,4-hydroxy-1-piperidinyl-CH₂—, 3-hydroxy-1-piperidinyl-CH₂—,2-ethoxycarbonyl-1-piperidinyl-CH₂—,3-ethoxycarbonyl-1-piperidinyl-CH₂—, 3-carboxy-1-piperidinyl-CH₂—,4-ethoxycarbonyl-1-piperidinyl-CH₂—, 4-carboxy-1-piperidinyl-CH₂—,4-(1-pyrrolidinyl)-1-piperidinyl-CH₂—,4-(N-hydroxyethylamino)-1-piperidinyl-CH₂—,4-(N-propylamino)-1-piperidinyl-CH₂—, 1-methyl-4-piperazinyl-CH₂—,4-morpholinyl-CH₂—, (2-methyl-1-imidazolyl-CH₂—,3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH₂—, phthalimidylethylenyl,1-azepanyl-CH₂—, 1,4-dioxa-8-aza-spiro[4.5]decyl-CH₂—,4-(methyl)phenoxymethylenyl,4-(N,N-dimethylaminomethylenyl)phenoxymethylenyl,methylaminothiocarbonyl, methoxymethylenyl, ethylaminothiocarbonyl,N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl,N-methylaminoethylenyl, N-methylaminomethylenyl,N-(hydroxypropyl)aminomethylenyl, N-ethylaminomethylenyl,Boc-aminoethoxymethylenyl, aminoethoxymethylenyl,(1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, 2-pyrrolidinylmethoxy,1-methyl-2-pyrrolidinylmethoxy, azetidin-3-ylmethoxy,N-Boc-azetidin-3-ylmethoxy, N-Boc-piperidin-4-ylethoxy,1-methyl-4-piperidinylethoxy, 4-piperidinylethoxy, 4-piperidinylmethoxy,N,N-dimethylaminoethoxy, 3-tetrahydrofuryl-O—, 3-tetrahydrofurylmethoxy,4-tetrahydrofurylmethoxy, 4-methylphenoxy, 4-(aminoethyl)phenoxy,4-(1-imidazolyl)phenoxy, 2,4-dimethylphenoxy, phenoxy, 4-cyanophenoxy,4-[1,3]dioxolan-2-ylphenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy,ethoxycarbonyl, morpholinylethylenylaminocarbonyl,morpholinylpropylenylaminocarbonyl, 1-piperidinylcarbonyl,methylaminocarbonyl, ethylaminocarbonyl, N,N-diethylaminocarbonyl,N-(N′,N′-dimethylaminoethylenyl)aminocarbonyl, aminocarbonyl,morpholinylethylenylamino, morpholinylpropylenylamino, N,N-diethylamino,N,N-dimethylamino, N,N-diethylamino(2-propylenyl)aminomethylenyl,N,N-diethylamino(1-propylenyl)aminomethylenyl andN-(N′,N′-dimethylaminoethylenyl)amino;

[0041] wherein Y is selected from

[0042] preferably Y is selected from

[0043] more preferable Y is selected from

[0044] even more preferably Y is

[0045] wherein R² is selected from

[0046] a) lower alkylaminoalkynyl,

[0047] b) cycloalkenyl-C₂₋₃-alkynyl,

[0048] c) cycloalkyl-C₂₋₃-alkynyl,

[0049] d) phenyl-C₂₋₃-alkynyl,

[0050] e) 5-6 membered heterocyclyl-C₂₋₃-alkynyl,

[0051] f) substituted or unsubstituted cycloalkenyl,

[0052] g) substituted or unsubstituted phenyl,

[0053] h) substituted or unsubstituted 5-6 membered heterocyclyl, and

[0054] i) substituted or unsubstituted 5-6 membered heterocyclyl bridgedwith a phenyl group,

[0055] preferably substituted phenyl, substituted or unsubstituted 5-6membered nitrogen-containing heteroaryl, and substituted orunsubstituted 5-6 membered nitrogen-containing heteroaryl fused with aphenyl group,

[0056] more preferably substituted or unsubstituted substituted phenylor a substituted or unsubstituted heterocyclyl substituent selected fromthiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl and quinolyl,

[0057] even more preferably phenyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, purinyl, isoquinolyl and quinolyl,

[0058] most preferably pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl,

[0059] preferred pyridyl;

[0060] wherein substituted R² is substituted with one or moresubstituents independently selected from halo, —OR₃, —SR³, —CO₂R³,—CO₂NR³R³, —COR³, —NR³R³, —C(O)NR³R³, —SO₂NR³R³, —NR³C(O)OR³, —NHC(O)R³,—SO₂NHC(O)R³, —C(S)NR³R³, nitro, cycloalkyl, optionally substitutedphenylalkylenyl, optionally substituted 4-7 membered heterocyclyl,optionally substituted heterocyclylalkylenyl, optionally substitutedphenyl, optionally substituted phenoxyalkylenyl, optionally substitutedheterocyclyloxyalkyl, lower alkyl, cyano, lower hydroxyalkyl, loweralkoxyalkyl, lower azidoalkyl, lower aminoalkyl, lower(hydroxyalkyl)aminoalkyl, lower alkylaminoalkyl, lower alkylaminoalkoxy,lower aminoalkoxyalkyl, lower (alkylaminoalkyl)amino lower((alkylamino)alkylamino)alkyl, lower alkylaminoalkylaminocarbonyl, lowercyanoalkyl, lower alkenyl, lower alkynyl and lower haloalkyl,

[0061] preferably selected from C₁-C₄ alkyl, C₁-C₂ haloalkyl, halo,amino, C₁-C₂-alkoxy, C₁-C₂-alkoxy-C₁-C₂-alkyl, hydroxy, C₁-C₂-alkylthio,cyano, C₁-C₂-haloalkyloxy, aminosulfonyl, (6-membered N-containingheterocyclyl)sulfonyl, C₁-C₂-haloalkylaminocarbonyl, nitro,C₁-C₂-haloalkylcarbonylaminosulfonyl, C₁-C₂-alkylaminosulfonyl,C₃-C₆-cycloalkylaminosulfonyl, phenyl-C₁-C₂-alkylaminosulfonyl,(optionally substituted phenyl)aminosulfonyl, piperidinyl, morpholinyl,C₁-C₂ alkylpiperazinyl, C₁-C₃ alkylaminothiocarbonyl,C₁-C₂-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,C₁-C₂-alkylcarbonylamino, morpholinyl-C₁-C₄-alkylenylamino,C₁-C₂-alkylamino and C₁-C₂-alkylamino-C₁-C₄-alkylenylamino,

[0062] more preferably selected from nitro, methylcarbonylamino,aminosulfonyl, phenylsulfonylamino, morpholinylsulfonyl,trifluoroacetylaminosulfonyl, (4-chlorophenyl)aminosulfonyl, hydroxy,methylthio, cyano, trifluoromethoxy, bromo, chloro, fluoro, amino,methoxy, ethoxy, ethoxymethyl, trifluoromethylcarbonylamino,trifluoroethoxy, pyridyl, phenyl, methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, isobutyl, tert-butyl, trifluoromethyl, difluoromethyl,pentafluoroethyl, carboxy, methylthio, piperidinyl, morpholinyl,N-methylpiperazinyl, N-ethylpiperazinyl, methylaminothiocarbonyl,N-methylamino-methylenyl, N,N-dimethylaminoethylenyl,N,N-diethylaminomethylenyl, N,N-dimethylamino, N-methylaminoethylenyl,N,N-diethylamino, morpholinylethylenylaminocarbonyl,morpholinylpropylenylaminocarbonyl, aminocarbonyl,morpholinylethylenylamino, morpholinylpropylenylamino, N,N-dimethylaminoand N,N-di-methylaminoethylenylamino;

[0063] wherein R³ is selected from H, lower alkyl, optionallysubstituted phenyl, optionally substituted phenylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,C₃-C₆ cycloalkyl, and lower haloalkyl,

[0064] preferably H, C₁-C₃ alkyl, phenyl, 5-6 membered heteroaryl, C₅-C₆cycloalkyl, and C₁-C₃ haloalkyl;

[0065] more preferably H, methyl, ethyl, optionally substituted phenyl,benzyl, and trifluoromethyl;

[0066] wherein R⁶ is selected from H, alkyl, 5-6 memberedheterocyclylalkylenyl and alkylamino,

[0067] preferably H;

[0068] wherein p is 1-2, preferably p is 1;

[0069] wherein q is 0 or 1; and

[0070] wherein r is 0, 1, 2 or 3, preferably 0 or 1, more preferably 0;

[0071] and pharmaceutically acceptable salts thereof;

[0072] provided A is not thiazol-2-yl when Y is ureido; further providedA is not phenyl when R² is pyridyl or pyrimidyl when Y is ureido andwhen X and Z taken together form 1-methylindolyl; further provided A isnot 1-phenylpyrazol-4-yl when Y is ureido when X and Z taken togetherform pyrazolyl and when R² is pyrrol-1-yl; further provided A is notthiazolyl or dihydrothiazolyl when R² is indolyl when Y is ureido andwhen X and Z taken together form thiazolyl or dihydrothiazolyl; providedA is not thiazolyl when R² is 3-pyridyl when Y is ureido and when X andZ taken together form 2-(3-pyridyl)thiazol-4-yl; and further provided Ais not thien-3-yl when Y is ureido when X and Z taken together formthienyl and when R² is pyrrol-1-yl.

[0073] The invention also relates to compounds of Formula Ia

[0074] The invention also relates to compounds of Formula I wherein A isselected from

[0075] preferably A is

[0076] and

[0077] wherein R is selected from H and C₁-C₃ alkyl; andpharmaceutically acceptable salts thereof.

[0078] The invention also relates to compounds of Formula II

[0079] wherein X¹ is CR¹ or N; wherein X² is CR¹ or N; wherein X³ is CHor N; provided only one of X¹, X² and X³ can be N;

[0080] wherein R¹ is one or more substituents selected from H,optionally substituted pyrrolidinyl, optionally substituted piperazinyl,optionally substituted piperidinyl, morpholinyl,1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C₁-C₆-alkyl,C₁-C₂-haloalkyl, C₁-C₄-hydroxyalkyl, amino, C₁-C₄-azidoalkyl,C₁-C₄-cyanoalkyl, C₁-C₄-aminoalkyl, halo, hydroxy, (optionallysubstituted pyrrolidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, morpholinyl-C₁-C₂-alkyl, (optionallysubstituted imidazolyl)-C₁-C₂-alkyl, phthalimidyl-C₁-C₂-alkyl,optionally substituted azepanyl-C₁-C₂-alkyl,1,4-dioxa-8aza-spiro[4.5]decyl-C₁-C₂-alkyl, optionally substitutedphenoxy-C₁-C₂-alkyl, C₁-C₄-alkylaminothiocarbonyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-hydroxyalkylamino-C₁-C₄-alkyl, amino-C₁-C₄-alkoxy-C₁-C₄-alkyl,(1-aza-bicyclo[2.2.2)oct-3-yl)-oxy, optionally substitutedpyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, optionally substitutedpiperidinyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy,tetrahydrofuryl-O—, tetrahydrofuryl-C₁-C₄-alkoxy, optionally substitutedpyridyloxy, optionally substituted phenoxy, C₁-C₄-alkoxycarbonyl,5-6-membered heterocyclyl-C₁-C₄-alkylaminocarbonyl, 5-6-memberedN-containing heterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl, aminocarbonyl, 5-6-memberedN-containing heterocyclyl-C₁-C₄-alkylamino, C₁-C₄-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkylamino-C₁-C₄-alkyl, andC₁-C₄-alkylamino-C₁-C₄-alkylamino;

[0081] wherein R² is selected from halo, C₁-C₄-alkyl,C₁-C₄-alkylamino-C₂-C₄-alkynyl, C₃-C₆-cycloalkyl, optionally substitutedbenzodioxolyl, optionally substituted indolyl, optionally substitutedphenoxy, unsubstituted 5-membered oxygen or sulfur containingheteroaryl, unsubstituted 6-membered nitrogen-containing heterocyclyl,phenyl optionally substituted with one or two substituents selected

[0082] from halo, C₁-C₄-alkylamino, amino, nitro, C₁-C₄-alkoxy,C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio, C₁-C₄-alkylcarbonylamino,(optionally substituted phenyl)sulfonylamino, cyano, C₁-C₂-haloalkoxy,5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-memberedN-containing heterocyclyl)sulfonyl, C₁-C₂-haloalkylcarbonylaminosulfonyland (optionally substituted phenyl)aminosulfonyl, and

[0083] 6-membered nitrogen-containing heterocyclyl substituted with oneor more substituents independently selected from pyridyl, phenyl,

[0084] C₁-C₄ alkyl, C₁-C₂ haloalkyl, C₁-C₂ alkoxy, amino, halo,piperidinyl, morpholinyl, C₁-C₂ alkylpiperazinyl, C₁-C₃alkylaminothiocarbonyl, N,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenyl,N—C₁-C₂-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,C₁-C₂-haloalkylcarbonylamino, morpholinyl-C₁-C₄-alkylenylamino,N,N-di-C₁-C₂-alkylamino andN,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenylamino; and

[0085] wherein Y² is selected from O, NH and CH₂;

[0086] and pharmaceutically acceptable salts thereof.

[0087] The invention also relates to compounds of Formula III

[0088] wherein X¹ is CR¹ or N; wherein X² is CR¹ or N; wherein X³ is CHor N; provided only one of X¹, X² and X³ can be N; preferably X¹ is CR¹;X² is CR¹; X³ is CH; provided X² is CH when X¹ is not CH;

[0089] wherein R¹ is one or more substituents independently selectedfrom H, optionally substituted pyrrolidinyl, optionally substitutedpiperazinyl, optionally substituted piperidinyl, morpholinyl,1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C₁-C₆-alkyl,C₁-C₂-haloalkyl, C₁-C₄-hydroxyalkyl, amino, C₁-C₄-azidoalkyl,C₁-C₄-cyanoalkyl, C₁-C₄-aminoalkyl, halo, hydroxy, (optionallysubstituted pyrrolidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, morpholinyl-C₁-C₂-alkyl, (optionallysubstituted imidazolyl)-C₁-C₂-alkyl, phthalimidyl-C₁-C₂-alkyl,optionally substituted azepanyl-C₁-C₂-alkyl,1,4-dioxa-8aza-spiro[4.5)decyl-C₁-C₂-alkyl, optionally substitutedphenoxy-C₁-C₂-alkyl, C₁-C₄-alkylaminothiocarbonyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-hydroxyalkylamino-C₁-C₄-alkyl, amino-C₁-C₄-alkoxy-C₁-C₄-alkyl,(1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substitutedpyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, optionally substitutedpiperidinyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy,tetrahydrofuryl-O—, tetrahydrofuryl-C₁-C₄-alkoxy, optionally substitutedpyridyloxy, optionally substituted phenoxy, C₁-C₄-alkoxycarbonyl,5-6-membered heterocyclyl-C₁-C₄-alkylaminocarbonyl, 5-6-memberedN-containing heterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl, aminocarbonyl, 5-6-memberedN-containing heterocyclyl-C₁-C₄-alkylamino, C₁-C₄-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkylamino-C₁-C₄-alkyl, andC₁-C₄-alkylamino-C₁-C₄-alkylamino, preferably H, methyl, ethyl, propyl,1-methyl-4-piperazinyl, 1-benzyl-4-piperazinyl,1-(2pyrimidinyl)-4-piperazinyl, 1-(2-pyridyl)-4-piperazinyl,1-ethyl-4-piperazinyl, 1-piperidinyl-CH₂—, 4-methyl-1-piperidinyl-CH₂—,3-methyl-1-piperidinyl-CH₂—, 2-methyl-1-piperidinyl-CH₂—,3,5-dimethyl-1-piperidinyl-CH₂—, 4-oxo-1-piperidinyl-CH₂—,4-hydroxy-1-piperidinyl-CH₂—, 3-hydroxy-1-piperidinyl-CH₂—,2-ethoxycarbonyl-1-piperidinyl-CH₂—,3-ethoxycarbonyl-1-piperidinyl-CH₂—, 3-carboxy-1-piperidinyl-CH₂—,4-ethoxycarbonyl-1-piperidinyl-CH₂—, 4-carboxy-1-piperidinyl-CH₂—,4-(1-pyrrolidinyl)-1-piperidinyl-CH₂—,4-(N-hydroxyethylamino)-1-piperidinyl-CH₂—,4-(N-propylamino)-1-piperidinyl-CH₂—,3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH₂—, 4-morpholinyl-CH₂—,N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl,N-methylaminomethylenyl, N-ethylaminomethylenyl and N,N-diethylamino,

[0090] more preferably ethyl, propyl, 1-methyl-4-piperazinyl,1-piperidinyl-CH₂—, 4-morpholinyl-CH₂—, N,N-diethylaminomethylenyl andN,N-diethylamino; and

[0091] wherein R² is selected from halo, C₁-C₄-alkyl,C₁-C₄-alkylamino-C₂-C₄-alkynyl, C₃-C₆-cycloalkyl, optionally substitutedbenzodioxolyl, optionally substituted indolyl, optionally substitutedphenoxy, unsubstituted 5-membered oxygen or sulfur containingheteroaryl, unsubstituted 5- or 6-membered nitrogen-containingheterocyclyl, phenyl optionally substituted with one or two substituentsselected

[0092] from halo, C₁-C₄-alkylamino, amino, nitro, C₁-C₄-alkoxy,C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio, C₁-C₄-alkylcarbonylamino,(optionally substituted phenyl)sulfonylamino, cyano, C₁-C₂-haloalkoxy,5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-memberedN-containing heterocyclyl)sulfonyl, C₁-C₂-haloalkylcarbonylaminosulfonyland (optionally substituted phenyl)aminosulfonyl, and

[0093] 6-membered nitrogen-containing heterocyclyl substituted with oneor more substituents independently selected from pyridyl, phenyl,

[0094] C₁-C₄ alkyl, C₁-C₂ haloalkyl, C₁-C₂ alkoxy, amino, halo,piperidinyl, morpholinyl, C₁-C₂ alkylpiperazinyl, C₁-C₃alkylaminothiocarbonyl, N,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenyl,N—C₁-C₂-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,C₁-C₂-haloalkylcarbonylamino, morpholinyl-C₁-C₄-alkylenylamino,N,N-di-C₁-C₂ alkylamino andN,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenylamino,

[0095] preferably 3-(N,N-dimethylamino)-1-propynyl, 3-fluorophenyl,4-fluorophenyl, 4-(N,N-dimethylamino)phenyl,3-(methylcarbonylamino)phenyl, phenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-aminophenyl, 3-aminophenyl,4-aminosulfonylphenyl, 4-(4-morpholinylsulfonyl)phenyl,4-(trifluoroacetylaminosulfonyl)phenyl,4-(trifluoromethylcarbonylaminosulfonyl)phenyl,4-[(4-chlorophenyl)aminosulfonyl]phenyl, 3-(phenylsulfonylamino)phenyl,2,4-difluorophenyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl,4-methylthiophenyl, 4-cyanophenyl, 4-trifluoromethoxyphenyl,4-methoxyphenyl, 3-nitrophenyl, 3-methoxyphenyl, 2-methoxyphenyl,2-thiazolyl, 2-pyrazinyl, 5-pyrimidinyl, 4-methyl-1-piperazinyl,4-morpholinyl, 6-methoxy-3-pyridyl, 2methoxy-3-pyridyl,2-ethoxy-3-pyridyl, 3,4-dichloro-4-pyridyl,6-(trifluoromethylcarbonylamino)-3-pyridyl, 6-amino-3-pyridyl,3,5-dichloro-4-pyridyl, 2-chloro-4-pyridyl, 3-pyridyl and 4-pyridyl,more preferably 5-pyrimidinyl, 2-pyrazinyl, morpholinyl,4-methylpiperazinyl, 4-fluorophenyl, 4-(N,N-dimethylamino)propynyl,3-nitrophenyl, 3-aminophenyl, 4-aminosulfonylphenyl,3-aminosulfonylphenyl, 3-(phenylsulfonylamino)phenyl,3-(methylcarbonylamino)phenyl,4-[(trifluoromethylcarbonyl)aminosulfonyl]phenyl, 4-hydroxyphenyl,4-methoxyphenyl, 2-thiazolyl,6-(trifluoromethylcarbonylamino)-3-pyridyl, 6-amino-3-pyridyl, 3-pyridyland 4-pyridyl;

[0096] and pharmaceutically acceptable salts thereof.

[0097] The invention also relates to compounds of Formula IV

[0098] wherein X¹ is CR¹ or N; wherein X² is CR¹ or N; wherein X³ is CHor N; provided only one of X¹, X² and X³ can be N; preferably X¹ is CR¹;X² is CR¹; X³ is CH; provided X² is CH when X¹ is not CH;

[0099] wherein R¹ is one or more substituents selected from H,optionally substituted pyrrolidinyl, optionally substituted piperazinyl,optionally substituted piperidinyl, morpholinyl,1,4-dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C₁-C₆-alkyl,C₁-C₂-haloalkyl, C₁-C₄-hydroxyalkyl, amino, C₁-C₄-azidoalkyl,C₁-C₄-cyanoalkyl, C₁-C₄-aminoalkyl, halo, hydroxy, (optionallysubstituted pyrrolidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, morpholinyl-C₁-C₂-alkyl, (optionallysubstituted imidazolyl)-C₁-C₂-alkyl, phthalimidyl-C₁-C₂-alkyl,optionally substituted azepanyl-C₁-C₂-alkyl,1,4-dioxa-8aza-spiro[4.5]decyl-C₁-C₂-alkyl, optionally substitutedphenoxy-C₁-C₂-alkyl, C₁-C₄-alkylaminothiocarbonyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-hydroxyalkylamino-C₁-C₄-alkyl, amino-C₁-C₄-alkoxy-C₁-C₄-alkyl,(1-aza-bicyclo[2.2.2]oct-3-yl)-oxy, optionally substitutedpyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, optionally substitutedpiperidinyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy,tetrahydrofuryl-O—, tetrahydrofuryl-C₁-C₄-alkoxy, optionally substitutedpyridyloxy, optionally substituted phenoxy, C₁-C₄-alkoxycarbonyl,5-6-membered heterocyclyl-C₁-C₄-alkylaminocarbonyl, 5-6-memberedN-containing heterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl, aminocarbonyl, 5-6-memberedN-containing heterocyclyl-C₁-C₄-alkylamino, C₁-C₄-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkylamino-C₁-C₄-alkyl, andC₁-C₄-alkylamino-C₁-C₄-alkylamino,

[0100] preferably methyl, ethyl, propyl, 1-methyl-4-piperazinyl,1-benzyl-4-piperazinyl, 1-(2-pyrimidinyl)-4-piperazinyl,1-(2-pyridyl)-4-piperazinyl, 1-ethyl-4-piperazinyl, 1-piperidinyl-CH₂—,4-methyl-1-piperidinyl-CH₂—, 3-methyl-1-piperidinyl-CH₂—,2-methyl-1-piperidinyl-CH₂—, 3,5-dimethyl-1-piperidinyl-CH₂—,4-oxo-1-piperidinyl-CH₂—, 4-hydroxy-1-piperidinyl-CH₂—,3-hydroxy-1-piperidinyl-CH₂—, 2-ethoxycarbonyl-1-piperidinyl-CH₂—,3-ethoxycarbonyl-1-piperidinyl-CH₂—, 3-carboxy-1-piperidinyl-CH₂—,4-ethoxycarbonyl-1-piperidinyl-CH₂—, 4-carboxy-1-piperidinyl-CH₂—,4-(1-pyrrolidinyl)-1-piperidinyl-CH₂—,4-(N-hydroxyethylamino)-1-piperidinyl-CH₂—,4-(N-propylamino)-1-piperidinyl-CH₂—,3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH₂—, 4-morpholinyl-CH₂—,N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl,N-methylaminomethylenyl, N-ethylaminomethylenyl and N,N-diethylamino,and

[0101] more preferably ethyl, propyl and 1-methyl-4-piperazinyl; and

[0102] wherein R² is halo, C₁-C₄-alkyl, C₁-C₄-alkylamino-C₂-C₄-alkynyl,C₃-C₆-cycloalkyl, optionally substituted benzodioxolyl, optionallysubstituted indolyl, optionally substituted phenoxy, 5-membered oxygenor sulfur containing heteroaryl, 5- or 6-membered nitrogen-containingheterocyclyl, phenyl optionally substituted with one or two substituentsselected

[0103] from halo, C₁-C₄-alkylamino, amino, C₁-C₄-alkoxy,C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio, cyano, C₁-C₂-haloalkyloxy,aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl,C₁-C₂-haloalkylcarbonylaminosulfonyl, and (optionally substitutedphenyl)aminosulfonyl, and

[0104] 6-membered nitrogen-containing heterocyclyl substituted with oneor more substituents

[0105] independently selected from pyridyl, phenyl, C₁-C₄ alkyl, C₁-C₂haloalkyl, C₁-C₂ alkoxy, halo, piperidinyl, morpholinyl, C₁-C₂alkylpiperazinyl, C₁-C₃ alkylaminothiocarbonyl,N,N-di-C₁-C₂_alkylamino-C₂-C₄-alkylenyl,N—C₁-C₂-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,morpholinyl-C₁-C₄-alkylenylamino, N,N-di-C₁-C₂-alkylamino andN,N-di-C₁-C₂_alkylamino-C₁-C₄-alkylenylamino, preferably 3-fluorophenyl,4-fluorophenyl, 4-(N,N-dimethylamino)phenyl,3-(methylcarbonylamino)phenyl, phenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 4-aminophenyl, 3-aminophenyl,4-aminosulfonylphenyl, 4-(4-morpholinylsulfonyl)phenyl,4-(trifluoroacetylaminosulfonyl)phenyl,4-(trifluoromethylcarbonylaminosulfonyl)phenyl,4-[(4-chlorophenyl)aminosulfonyl]phenyl, 3-(phenylsulfonylamino)phenyl,2,4-difluorophenyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 3-ethoxyphenyl, 3,4-dimethoxyphenyl,4-methylthiophenyl, 4-cyanophenyl, 4-trifluoromethoxyphenyl,4-methoxyphenyl, 3-nitrophenyl, 3-methoxyphenyl, 2-methoxyphenyl,2-thiazolyl, 2-pyrazinyl, 5-pyrimidinyl, 4-methyl-1-piperazinyl,4-morpholinyl, 6-methoxy-3-pyridyl, 2methoxy-3-pyridyl,2-ethoxy-3-pyridyl, 3,4-dichloro-4-pyridyl,6-(trifluoromethylcarbonylamino)-3-pyridyl, 6-amino-3-pyridyl,3,5-dichloro-4-pyridyl, 2-chloro-4-pyridyl, 3-pyridyl and 4-pyridyl, and

[0106] more preferably 4-pyridyl;

[0107] and pharmaceutically acceptable salts thereof.

[0108] The invention also relates to compounds of Formula V

[0109] wherein R⁷ is selected from halo, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,optionally substituted benzodioxolyl, optionally substituted indolyl,optionally substituted phenoxy, 5-membered oxygen or sulfur containingheteroaryl, 6-membered nitrogen-containing heterocyclyl, phenyloptionally substituted with one or two substituents selected

[0110] from halo, C₁-C₄-alkylamino, amino, C₁-C₄-alkoxy,C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio, cyano, C₁-C₂-haloalkyloxy,aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl,C₁-C₂-haloalkylcarbonylaminosulfonyl, and (optionally substitutedphenyl)aminosulfonyl, and

[0111] 6-membered nitrogen-containing heterocyclyl substituted with oneor more substituents

[0112] independently selected from pyridyl, phenyl, C₁-C₄ alkyl, C₁-C₂haloalkyl, C₁-C₂ alkoxy, halo, piperidinyl, morpholinyl, C₁-C₂alkylpiperazinyl, C₁-C₃ alkylaminothiocarbonyl,N,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenyl,N—C₁-C₂-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,morpholinyl-C₁-C₄-alkylenylamino, N,N-di-C₁-C₂_alkylamino andN,N-di-C₁-C₂_alkylamino-C₁-C₄-alkylenylamino,

[0113] preferably halo, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, optionallysubstituted pyrimidinyl, morpholinyl, optionally substitutedpiperidinyl, optionally substituted benzodioxolyl, optionallysubstituted indolyl, optionally substituted phenoxy, optionallysubstituted thienyl, phenyl optionally substituted with one or twosubstituents

[0114] selected from halo, C₁-C₄-alkylamino, Boc-amino, amino,C₁-C₄-alkoxy, C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio, cyano,C₁-C₂-haloalkyloxy, aminosulfonyl, (6-membered N-containingheterocyclyl)sulfonyl, C₁-C₂haloalkylcarbonylaminosulfonyl, and(optionally substituted phenyl)aminosulfonyl,

[0115] and pyridyl optionally substituted with one or two substituentsselected from C₁-C₃ alkyl, C₁-C₄-alkoxy and halo,

[0116] more preferably bromo, chloro, fluoro, C₁-C₃-alkyl,C₃-C₆-cycloalkyl, optionally substituted pyrimidinyl, morpholinyl,piperidinyl, benzodioxolyl, indolyl, phenoxy, thienyl, phenyl optionally

[0117] substituted with one or two substituents selected from fluoro,N,N-dimethylamino, amino, methoxy, trifluoromethyl, Boc-amino, hydroxy,ethoxy, methylthio, cyano, trifluoromethoxy, aminosulfonyl,4-morpholinylsulfonyl, trifluoroacetylaminosulfonyl, and(4-chlorophenyl)aminosulfonyl,

[0118] and pyridyl optionally substituted with one or two substituentsselected from C₁-C₃ alkyl, methoxy, ethoxy and chloro,

[0119] even more preferably bromo, methyl, ethyl, cyclopropyl,cyclohexyl, 3-fluorophenyl, 4-fluorophenyl, 4-(N,N-dimethylamino)phenyl,phenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-aminophenyl,3-aminophenyl, 4-Boc-aminophenyl, 4-aminosulfonylphenyl,4-(4-morpholinylsulfonyl)phenyl, 4-(trifluoroacetylaminosulfonyl)phenyl,4-[(4-chlorophenyl)aminosulfonyl]phenyl, 2,4-difluorophenyl,5-benzodioxolyl, 2,4-dimethoxyphenyl, 3-hydroxyphenyl, 3-ethoxyphenyl,3,4-dimethoxyphenyl, 4-methylthiophenyl, 5-indolyl, 4-cyanophenyl,4-trifluoromethoxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl,2-methoxyphenyl, phenoxy, 2-thienyl, 4-pyrimidinyl,2-methylthio-4-pyrimidinyl, morpholinyl, 4-piperidinyl,6methoxy-3-pyridyl, 2-methoxy-3-pyridyl, 2ethoxy-3-pyridyl,3,4-dichloro-4-pyridyl, 3,5-dichloro-4-pyridyl, 2-chloro-4-pyridyl,3-pyridyl and 4-pyridyl; and

[0120] wherein R⁸ is selected from

[0121] preferably

[0122] more preferably

[0123] and even more preferably

[0124] wherein R⁸ is optionally substituted with one or two substituentsindependently selected from H, optionally substituted pyrrolidinyl,optionally substituted piperazinyl, optionally substituted piperidinyl,morpholinyl, 1,4-dioxa-8-aza-spiro(4.5]decyl, pyridyl, phenyl,C₁-C₆-alkyl, C₁-C₂-haloalkyl, C₁-C₄-hydroxyalkyl, amino,C₁-C₄-azidoalkyl, C₁-C₄-cyanoalkyl, C₁-C₄-aminoalkyl, halo, hydroxy,((optionally substituted pyrrolidinyl)-C₁-C₂-alkyl, (optionallysubstituted piperidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, morpholinyl-C₁-C₂-alkyl, (optionallysubstituted imidazolyl) -C₁-C₂-alkyl, phthalimidyl-C₁-C₂-alkyl,optionally substituted azepanyl-C₁-C₂-alkyl,1,4-dioxa-8-aza-spiro(4.5]decyl-C₁-C₂-alkyl, optionally substitutedphenoxy-C₁-C₂-alkyl, C₁-C₄-alkylaminothiocarbonyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-hydroxyalkylamino-C₁-C₄-alkyl, amino-C₁-C₄-alkoxy-C₁-C₄-alkyl,(1-azabicyclo[2.2.2]oct-3-yl)-oxy, optionally substitutedpyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, optionally substitutedpiperidinyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy,tetrahydrofuryl-O—, tetrahydrofuryl-C₁-C₄-alkoxy, optionally substitutedpyridyloxy, optionally substituted phenoxy, C₁-C₄-alkoxycarbonyl,5-6-membered heterocyclyl-C₁-C₄-alkylaminocarbonyl, 5-6-memberedN-containing heterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl, aminocarbonyl, 5-6-memberedN-containing heterocyclyl-C₁-C₄-alkylamino, C₁-C₄-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkylamino-C₁-C₄-alkyl, andC₁-C₄-alkylamino-C₁-C₄-alkylamino,

[0125] preferably unsubstituted or substituted with one or moresubstituents selected from pyridyl, phenyl, C₁C₄ alkyl, C₁-C₂ haloalkyl,halo, piperidinyl, morpholinyl, methylpiperazinyl,methylaminothiocarbonyl, N,N-diethylaminomethylenyl,N-methylaminomethylenyl, morpholinylpropylenylaminocarbonyl,aminocarbonyl morpholinylpropylenylamino, N,N-diethylamino andN,N-dimethylaminoethylenylamino;

[0126] wherein R⁹ is selected from optionally substituted pyrrolidinyl,optionally substituted piperazinyl, optionally substituted piperidinyl,morpholinyl, 1,4dioxa-8-aza-spiro[4.5]decyl, pyridyl, phenyl, C₁-C₄alkyl, C₁-C₂ haloalkyl, C₁-C₂ hydroxyalkyl, amino, C₁-C₂ azidoalkyl,C₁-C₂ cyanoalkyl, C₁-C₂ aminoalkyl, halo, (optionally substitutedpyrrolidinyl)CH₂—, (optionally substituted piperidinyl)-CH₂—,(optionally substituted piperazinyl)-CH₂—, 4-morpholinyl-CH₂—,(optionally substituted imidazolyl)-CH₂—, phthalimidylethyl, optionallysubstituted azepanyl-CH₂—, 1,4-dioxa-8-aza-spiro[4.5]decyl-CH₂—,optionally substituted phenoxy-CH₂—, C₁-C₄-alkylaminothiocarbonyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄-hydroxyalkylamino-C₂-C₄-alkyl, Boc-aminoethoxymethylenyl,amino-C₁-C₄-alkoxy-C₁-C₄-alkyl, (1-aza-bicyclo[2.2.2]oct-3-yl)-oxy,optionally substituted pyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, optionally substitutedpiperidinyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy,tetrahydrofuryl-O—, tetrahydrofuryl-C₁-C₄-alkoxy, optionally substitutedphenoxy, C₁-C₄-alkoxycarbonyl, heterocyclyl-C₁-C₄-alkylaminocarbonyl,1-piperidinylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl, aminocarbonyl,morpholinyl-C₁-C₄-alkylamino, C₂-C₄-alkylamino,C₃-C₄alkylamino-C₁-C₄-alkylamino-C₁-C₄-alkyl, andC₁-C₄alkylamino-C₁-C₄-alkylamino,

[0127] preferably 3-(N,N-dimethylamino)-1-pyrrolidinyl,1-methyl-4-piperazinyl, 1-benzyl-4-piperazinyl,1-(2-pyrimidinyl)-4-piperazinyl, 1-(2-pyridyl)-4-piperazinyl,1-ethyl-4-piperazinyl, 4-amino-1-piperidinyl,4-(N-hydroxyethylamino)-1-piperidinyl, 4-(N-propylamino)-1-piperidinyl,4-(N-benzylamino)-1-piperidinyl, 4-oxo-piperidinyl,4-(hydroxyimino)piperidinyl, 4-morpholinyl,1,4-dioxa-8-azaspiro[4.5]decyl, pyridyl, phenyl, methyl, ethyl, propyl,amino, azidomethyl, hydroxymethyl, trifluoromethyl, fluoro, chloro,bromo, aminoethyl, aminomethyl, cyanomethyl, 1-pyrrolidinyl-CH₂—,2-methoxycarbonyl-1-pyrrolidinyl-CH₂—, 2-carboxy-1-pyrrolidinyl-CH₂—,2-hydroxymethyl-1-pyrrolidinyl-CH₂—, 1-piperidinyl-CH₂—,4-methyl-1-piperidinyl-CH₂—, 3-methyl-1-piperidinyl-CH₂—,2-methyl-1-piperidinyl-CH₂—, 3,5-dimethyl-1-piperidinyl-CH₂—,4-oxo-1-piperidinyl-CH₂—, 4-hydroxy-1-piperidinyl-CH₂—,3-hydroxy-1-piperidinyl-CH₂—, 2-ethoxycarbonyl-1-piperidinyl-CH₂—,3-ethoxycarbonyl-1-piperidinyl-CH₂—, 3-carboxy-1-piperidinyl-CH₂—,4-ethoxycarbonyl-1-piperidinyl-CH₂—, 4-carboxy-1-piperidinyl-CH₂—,4-(1-pyrrolidinyl)-1-piperidinyl-CH₂—,4-(N-hydroxyethylamino)-1-piperidinyl-CH₂—,4-(N-propylamino)-1-piperidinyl-CH₂—, 1-methyl-4-piperazinyl-CH₂—,4-morpholinyl-CH₂—, (2-methyl-1-imidazolyl-CH₂—,3-(N,N-diethylamino)carbonyl-1-piperidinyl-CH₂—, phthalimidylethyleneyl,1-azepanyl-CH₂—, 1,4-dioxa-8-aza-spiro(4.5]decyl-CH₂—,4-(methyl)phenoxymethylenyl,4-(N,N-dimethylaminomethylenyl)phenoxymethylenyl,methylaminothiocarbonyl, methoxymethylenyl, ethylaminothiocarbonyl,N,N-dimethylaminoethylenyl, N,N-diethylaminomethylenyl,N-methylaminomethylenyl, N-(hydroxypropyl)aminomethylenyl,N-ethylaminomethylenyl, Boc-aminoethoxymethylenyl,aminoethoxymethylenyl, (1-aza-bicyclo[2.2.2]oct-3-yl)oxy,2-pyrrolidinylmethoxy, 1-methyl-2-pyrrolidinylmethoxy,azetidin-3-ylmethoxy, N-Boc-azetidin-3-ylmethoxy,N-Boc-piperidin-4-ylethoxy, 1methyl-4-piperidinylethoxy,4-piperidinylethoxy, 4-piperidinylmethoxy, N,N-dimethylaminoethoxy,3-tetrahydrofuryl-O—, 3-tetrahydrofurylmethoxy,4-tetrahydrofurylmethoxy, 4-methylphenoxy, 4-(aminoethyl)phenoxy,4-(1-imidazolyl)phenoxy, 2,4-dimethylphenoxy, phenoxy, 4-cyanophenoxy,4-[1,3]dioxolan-2-ylphenoxy, 4-fluorophenoxy, 3,4-difluorophenoxy,ethoxycarbonyl, morpholinylpropylenylaminocarbonyl,1-piperidinylcarbonyl, methylaminocarbonyl, ethylaminocarbonyl,N,N-diethylaminocarbonyl, N-(N′,N′-dimethylaminoethylenyl)aminocarbonyl,aminocarbonyl, morpholinylpropylenylamino, N,N-diethylamino,N,N-diethylamino(2-propylenyl)aminomethylenyl,N,N-diethylamino(1-propylenyl)aminomethylenyl andN-(N′,N′-dimethylaminoethylenyl)amino;

[0128] wherein R¹⁰ is selected from H, hydroxy, and amino;

[0129] wherein R¹¹ is selected from pyridyl and pyrimidinyl, preferablypyridyl; and

[0130] wherein R¹² is selected from H, and C₁-C₄ alkyl,

[0131] preferably H, methyl, ethyl and propyl;

[0132] and pharmaceutically acceptable salts thereof.

[0133] The invention also relates to compounds of Formula VI

[0134] wherein R¹⁵ is one or more substituents selected from H,optionally substituted heterocyclyl, phenyl, C₁-C₆-alkyl,C₁-C₂-haloalkyl, C₁-C₄-hydroxyalkyl, amino, C₁-C₄-azidoalkyl,C₁-C₄-cyanoalkyl, C₁-C₄-aminoalkyl, halo, hydroxy, (optionallysubstituted heterocyclyl)-C₁-C₄-alkyl, optionally substitutedphenoxy-C₁-C₂-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-hydroxyalkylamino,amino-C₁-C₄-alkoxy-C₁-C₄-alkyl, optionally substituted heterocyclyloxy,optionally substituted heterocyclyl-C₁-C₄-alkoxy,C₁-C₄-alkylamino-C₁C₄-alkoxy, optionally substituted phenoxy,C₁-C₄-alkoxycarbonyl, 5-6-memberedheterocyclyl-C₁-C₄-alkylaminocarbonyl, 5-6-membered N-containingheterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylaminothiocarbonyl, C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl,aminocarbonyl, 5-6-membered N-containingheterocyclyl-sulfonyl-C₁-C₄-alkyl, 5-6-membered N-containingheterocyclyl-C₁-C₄-alkylamino, C₁-C₄-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkylamino-C₁-C₄-alkyl, andC₁-C₄-alkylamino-C₁-C₄-alkylamino;

[0135] preferably H, optionally substituted pyrrolidinyl, optionallysubstituted piperazinyl, optionally substituted piperidinyl,morpholinyl, 1,2,3,6-tetrahydro-pyridinyl, (optionally substitutedpyrrolidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, morpholinyl-C₁-C₂-alkyl,C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-hydroxyalkylamino, (optionallysubstituted pyrrolidinyl)-C₁-C₂-alkylamino, (optionally substitutedpiperidinyl)-C₁-C₂-alkylamino, (optionally substitutedpiperazinyl)-C₁-C₂-alkylamino, morpholinyl-C₁-C₂-alkylamino, optionallysubstituted pyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, tetrahydrofuryl-C₁-C₄-alkoxy, optionallysubstituted piperidinyl-C₁-C₄-alkoxy, C₁-C₄alkylamino-C₁-C₄-alkoxy,tetrahydrofuryloxy, optionally substituted piperidinyloxy, optionallysubstituted phenoxy, C₁-C₄-alkylaminocarbonyl andC₁-C₄-alkylaminothiocarbonyl;

[0136] more preferably H, tetrahydro-furanyloxy,1-methylpyrrolidin-2-ylmethoxy, 2-pyrrolidinylmethoxy,3-pyrrolidinylmethoxy, 1-Boc-pyrrolidin-2-ylmethoxy,4-piperidinylmethoxy, 1-Boc-piperidin-4-ylmethoxy,1-Boc-piperidin-4-ylethoxy, piperidin-4-ylethoxy,1-methyl-piperidin-4-ylmethoxy, 1-Boc-azetidin-3-ylmethoxy,1-methyl-azetidin-3-ylmethoxy, 3-azetidinylmethoxy,1-methyl-piperidin-4-yloxy, phenyloxy, 4-(pyrrolidin-1-ylmethyl)phenoxy,dimethylaminoethoxy, piperidinylethylamino, 1-piperidinylmethyl,1-(piperidin-1-yl)ethyl, 3-methylpiperidin-1-ylmethyl,1-pyrrolidinylmethyl, 2,2,6,6-tetramethylpiperidin-1-ylmethyl,2,6-dimethylpiperidin-1-ylmethyl, dimethylaminomethyl,diethylaminomethyl, diethylaminothiocarbonyl, diethylaminocarbonyl,N-Boc-N-isopropylaminomethyl, isopropylaminomethyl,2-thienylsulfonylmethyl, hydroxypropylamino, 4-ethyl-piperidin-1-yl,4-(2-pyridyl)piperidin-1-yl, 1-methylpiperidin-4-yl,4-(2-pyrazinyl)piperidin-1-yl, 1-methyl-1,2,3,6-tetrahydropyridin-4-yl,1,2,3,6-tetrahydro-pyridin-4-yl, and1Boc-1,2,3,6-tetrahydro-pyridin-4-yl;

[0137] wherein R¹⁶ is selected from H, heterocyclylcarbonyl,alkylaminocarbonyl, alkylaminomethyl, and heterocyclylmethyl;

[0138] preferably H, 5-6-membered nitrogen containingheterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkylaminomethyl,and 5-6-membered nitrogen containing heterocyclylmethyl;

[0139] more preferably H, 1-piperidinylcarbonyl, diethylaminocarbonyl,diethylaminomethyl, 1-piperidinylmethyl; and

[0140] wherein R¹⁷ is selected from halo, and preferably chloro andbromo, C₁-C₃-alkyl, preferably C₁-C₂-alkyl, and more preferably methyl,

[0141] cycloalkylalkynyl, preferably C₃-C₆-cycloalkyl-C₂-C₄-alkynyl, andmore preferably cyclopropylethynyl, cycloalkyl, preferablyC₃-C₆-cycloalkyl, and more preferably cyclopropyl,

[0142] optionally substituted heteroarylsulfonyl-C₁-C₄-alkyl, andpreferably optionally substituted 5-6-memberedheteroarylsulfonyl-C₂-C₂-alkyl,

[0143] optionally substituted indolyl, and preferably 1-Boc-indol-5-yl,

[0144] optionally substituted phenoxy,

[0145] optionally substituted indazolyl, and preferably 5-indazolyl,

[0146] unsubstituted 5-membered oxygen or sulfur containing heteroaryl,and preferably unsubstituted thienyl, and 5-tert-butyloxazol-2-yl,

[0147] unsubstituted 6-membered nitrogen-containing heterocyclyl,

[0148] phenyl optionally substituted with one or two substituentsselected from halo, C₁-C₄-alkylamino, amino, nitro, C₁-C₄-alkoxy,C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio, C₁-C₄-alkylcarbonylamino,(optionally substituted phenyl)sulfonylamino, cyano, C₁-C₂-haloalkoxy,5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-memberedN-containing heterocyclyl)sulfonyl, C₁-C₂-haloalkylcarbonylaminosulfonyland (optionally substituted phenyl)aminosulfonyl, and

[0149] preferably optionally substituted with one or two substituentsselected from halo, C₁-C₄-alkylamino, amino, nitro, C₁-C₄-alkoxy,C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio, C₁-C-₄-alkylcarbonylamino,(optionally substituted phenyl)sulfonylamino, cyano, C₁-C₂-haloalkoxy,5- or 6-membered N-containing heterocyclyl, aminosulfonyl, (6-memberedN-containing heterocyclyl)sulfonyl, C₁-C₂-haloalkylcarbonylaminosulfonyland (optionally substituted phenyl)aminosulfonyl; and more preferablyand phenyl optionally substituted with aminosulfonyl, and

[0150] 6-membered nitrogen-containing heterocyclyl substituted with oneor more substituents independently selected from pyridyl, phenyl, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, amino, halo, piperidinyl,morpholinyl, C₁-C₄ alkylpiperazinyl, C₁-C₄ alkylaminothiocarbonyl,N,N-di-C₁-C₄-alkylamino-C₁-C₄-alkylenyl,N-C₁-C₄-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,C₁-C₄-haloalkylcarbonylamino, morpholinyl-C₁-C₄-alkylenylamino,N,N-di-C₁-C₂-alkylamino andN,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenylamino;

[0151] preferably pyridyl, phenyl, C₁-C₄ alkyl, C₁-C₂ haloalkyl, C₁-C₂alkoxy, amino, halo, piperidinyl, morpholinyl, C₁-C₂ alkylpiperazinyl,C₁-C₃ alkylaminothiocarbonyl, N,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenyl,N-C₁-C₂ alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,C₁-C₂-haloalkylcarbonylamino, morpholinyl-C₁-C₄-alkylenylamino,N,N-di-Cl-C₂-alkylamino and N,Ndi-C₁-C₂-alkylamino-C₁-C₄-alkylenylamino,and

[0152] more preferably 4-pyridyl substituted with one or moresubstituents independently selected from methoxy and chloro;

[0153] and pharmaceutically acceptable derivatives thereof;

[0154] provided only one of R¹⁵ and R¹⁶ is H.

[0155] A family of specific compounds of particular interest withinFormula I consists of compounds and pharmaceutically-acceptable saltsthereof as follows:

[0156]1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;

[0157]1-[4-(Piperidine-1-carbonyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0158]1-(2-Chloro-thiazol-4-yl)-3-(4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;

[0159]N,N-Diethyl-2-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-isonicotinamide;

[0160] N,N-Diethyl-2-[3-(2-phenyl-thiazol-4-yl)-ureido]-isonicotinamide;

[0161] 2-[3-(2-Bromo-thiazol-4-yl)-ureido]-N,N-diethyl-isonicotinamide;

[0162]1-(4-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0163]1-[6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0164]1-[6-(1-Piperidin-1-yl-ethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0165]2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;

[0166]1-{6-[(Piperidin-2-ylmethyl)-amino]-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0167](S)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0168](R)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0169]1-(2-Chloro-thiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;

[0170]1-(2-Bromo-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;

[0171]1-(2-Chloro-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;

[0172]1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-bromo-thiazol-4-yl)-urea;

[0173]1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-chloro-thiazol-4-yl)-urea;

[0174]1-(2-Bromo-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;

[0175]1-(2-Chloro-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;

[0176]3-(4-{3-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-ureido}-thiazol-2-yl)-benzenesulfonamide;

[0177] tert-Butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylate;

[0178]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-3-ylmethoxy)-pyridin-2-yl]-urea;

[0179]1-(2-Cyclopropyl-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;

[0180]1-[6-(Isopropylamino-methyl)-pyridin-2-yl-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0181]Isopropyl-{6-(3-(2-phenyl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamicacid tert-butyl ester;

[0182]1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;

[0183]1-(2-Bromo-thiazol-4-yl)-3-[6-(isopropylamino-methyl)-pyridin-2-yl]-urea;

[0184]1-(2-Bromo-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;

[0185]1-(2-Chloro-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;

[0186]1-(2-phenylthiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;

[0187]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-urea;

[0188]1-[2-(1H-Indazol-5-yl)-thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;

[0189]1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0190]1-(2-Bromo-thizol-4-yl)-3-(1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea;

[0191]1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-2-[2,4]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)urea;

[0192]1-[6-(3-Hydroxy-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thizol-4-yl)-urea;

[0193]1-(2-Bromo-thiazol-4-yl)-3-(6(3-hydroxy-propylamino)-pyridin-2-yl]-urea;

[0194]1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipydrinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0195]1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea;

[0196]6-[3-(2-Pyridin-4-yl-thizol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylicacid tert-butyleester;

[0197]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea;

[0198]1-(2-Pyridin-4-yl-thizol-4-yl)-3-[6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-yl]-urea;

[0199]2-[6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl]-pyrrolidine-1-carbooxylicacid tert-butyl ester;

[0200]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;

[0201] 6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridine-2-carbothioicacid diethylamide;

[0202]1-(2-Bromo-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;

[0203]1-(2-Chloro-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;

[0204]1-(2-Phenyl-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;

[0205]1-(2-Bromo-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;

[0206]1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-phenoxy-pyridin-2-yl)-urea;

[0207]1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;

[0208]1-[6-(2-Dimethylamino-ethoxy)-pyridin-2-yll-3-[2-(2-methoxy-pyridin-4-yl)-thiazol-4-yl]-urea;

[0209]1-(2-phenylthiazol-4-yl)-3-(6-pyrrolidin-1-ylmethyl-pyridin-2-yl)urea;

[0210]1-(6-Diethylaminomethylpyridin-2-yl)-3-(2-phenylthiazol-4-yl)urea;

[0211](S)-1-[6-(1-Methylpyrrolidin-2-ylmethoxy)pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea;

[0212]1-[6-(2-Piperidin-4-yl-ethoxy)pyridin-2-yl]-3-[2-phenylthiazol-4-yl]urea;

[0213]1-[6-(4-Ethylpiperazin-1-yl)-pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea;

[0214]1-(2-phenylthiazol-4-yl)-3-[6-(4-pyrimidin-2-yl-piperazin-1-yl)pyridin-2-yl]urea;

[0215] Diethyl6-[3-(2-phenylthiazol-4-yl)ureido]-pyridine-2-carboxamide;

[0216]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;

[0217]1-(2-Bromothiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;

[0218]1-[6-(Piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0219]1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0220]1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-y1]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0221]1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;

[0222]1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;

[0223]1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;

[0224]1-(2-Phenyl-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;

[0225]1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;

[0226]1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;

[0227]1-[6-(2-Piperidin-4-yl-ethoxy)-pyridin-2-yl]-3-(2-thiophen-2-yl-thiazol-4-yl)-urea;

[0228]1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-[2-(thiophene-2-sulfonylmethyl)-thiazol-4-yl]-urea;

[0229]1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea;and

[0230][2-(2-Chloro-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea.

[0231] Indications

[0232] Compounds of the present invention would be useful for, but notlimited to, the treatment of cell proliferative diseases or ofapoptosis.

[0233] The compounds of the invention are endowed with kinase inhibitoryactivity, such as CDK/cyclin kinase inhibitory activity and GSKinhibitory activity.

[0234] The compounds of the invention are useful in therapy asantineoplasia agents.

[0235] Compounds of the invention would be useful for the treatment ofneoplasia including cancer, including, but not limited to: carcinomasuch as cancer of the bladder, breast, colon, kidney, liver, lung(including small cell lung cancer), esophagus, gall-bladder, ovary,pancreas, stomach, cervix, thyroid, prostate, and skin (includingsquamous cell carcinoma); hematopoietic tumors of lymphoid lineage(including leukemia, acute lymphocitic leukemia, acute lymphoblasticleukemia, B-cell lymphoma, T-cell-Lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma);hematopoietic tumors of myeloid lineage (including acute and chronicmyelogenous leukemias, myelodysplastic syndrome and promyelocyticleukemia); tumors of mesenchymal origin (including fibrosarcoma andrhabdomyosarcoma, and other sarcomas, e.g. soft tissue and bone); tumorsof the central and peripheral nervous system (including astrocytoma,neuroblastoma, glioma and schwannomas); and other tumors (includingmelanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderomapigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi'ssarcoma).

[0236] Preferably, the compounds are useful for the treatment ofneoplasia selected from lung cancer, colon cancer and breast cancer.

[0237] Due to the key role of CDKs in the regulation of cellularproliferation, these compounds are also useful in the treatment of avariety of cell proliferative disorders such as, for instance, bloodvessel proliferative disorders including arthritis and restenosis;fibrotic disorders including hepatic cirrhosis and atherosclerosis;mesangial cell proliferative disorders including glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathy syndromes, transplant rejection and glomerulopathies;metabolic disorders including psoriasis, diabetes mellitus, chronicwound healing, inflammation, and diabetic retinopathy and other visiondisorders; and others including benign prostate hyperplasia, familialadenomatosis polyposis, neuro-fibromatosis, pulmonary fibrosis,angiogenesis, metastasis, vascular smooth cell proliferation,post-surgical stenosis and hypertrophic scar formation, eczema,inflammatory bowel disease, endotoxic shock, and fungal infections.

[0238] The compounds of the invention are useful to prevent thephosphorylation of tau protein.

[0239] The compounds of the invention are useful in the treatment ofneurological disorders, including neurological injuries andneurodegenerative diseases, such as, but not limited to, stroke, braintrauma, epilepsy, spinal cord injury, ischemia, multiple sclerosis,vision related disorders including but not limited to glaucoma andmacular degeneration, hearing loss, AIDS-related dementia, retinitispigmentosa, spinal muscular atrophy, cerebellar degeneration,amyotrophic lateral sclerosis, Parkinson's disease, Huntington's diseaseand Alzheimer's disease.

[0240] Compounds of Formula I-VI, as inhibitors of the CDKs, canmodulate the level of cellular RNA and DNA synthesis. These agents wouldtherefore be useful in the treatment of viral infections, including butnot limited to HIV, human papilloma virus, herpesvirus, poxvirus,Epstein-Barr virus, Sindbis virus and adenovirus.

[0241] The compounds of this invention may also act as inhibitors ofother protein kinases, e.g. KDR, IKK, JNK3, and thus be effective in thetreatment of diseases associated with other protein kinases.

[0242] Besides being useful for human treatment, these compounds arealso useful for veterinary treatment of companion animals, exoticanimals and farm animals, including mammals, rodents, and the like. Morepreferred animals include horses, dogs, and cats.

[0243] Inhibitors of certain kinases may have utility in the treatmentof diseases when the kinase is not misregulated, but is nonethelessessential for maintenance of the disease state. In this case, inhibitionof the kinase activity would act either as a cure or palliative forthese diseases. For example, many viruses, such as human papillomavirus, disrupt the cell cycle and drive cells into the S-phase of thecell cycle. Preventing cells from entering DNA synthesis after viralinfection by inhibition of essential S-phase initiating activities suchas CDK2, may disrupt the virus life cycle by preventing virusreplication. This same principle may be used to protect normal cells ofthe body from toxicity of cycle-specific chemotherapeutic agents.Inhibition of CDK2 or CDK4 will prevent progression into the cycle innormal cells and limit the toxicity of cytotoxics which act in S-phase,G2 or mitosis. Furthermore, CDK2/cyclin E activity has also been shownto regulate NF-κB: Inhibition of CDK2 activity stimulatesNF-κB-dependent gene expression, an event mediated through interactionswith the p300 coactivator. NF-κB regulates genes involved ininflammatory responses, (such as hematopoietic growth factors chemokinesand leukocyte adhesion molecules) and may be involved in the suppressionof apoptotic signals within the cell. Thus, inhibition of CDK2 maysuppress apoptosis induced by cytotoxic drugs via a mechanism whichinvolves NF-κB. Inhibition of CDK2 activity may also have utility inother cases where regulation of NF-κB plays a role in etiology ofdisease. A further example may be taken from fungal infections:Inhibition of the Aspergillus kinases Cdc2/CDC28 or Nim A may causearrest or death in the fungi, improving the therapeutic outcome forpatients with these infections.

[0244] The compounds of the invention are useful as modulators ofapoptosis. As such they are useful in the prevention of AIDS developmentin HIV-infected individuals, autoimmune diseases (including but notlimited to systemic lupus, erythematosus, autoimmune mediatedglomerulonephritis, rheumatoid arthritis and autoimmune diabetesmellitus), myelodysplastic syndromes, aplastic anemia, ischemic injuryassociated with myocardial infarctions, stroke and reperfusion injury,vision related disorders including but not limited to glaucoma andmacular degeneration, arrhythmia, atherosclerosis, toxin-induced oralcohol related liver diseases, hematological diseases (including butnot limited to chronic anemia and aplastic anemia), degenerativediseases of the musculoskeletal system (including but not limited toosteoporosis) aspirin-sensitive rhinosinusitis, cystic fibrosis, kidneydiseases and cancer pain.

[0245] Definitions

[0246] The term “prevention” includes either preventing the onset ofdisorders altogether or delaying the onset of a preclinically evidentstage of disorders in individuals. This includes prophylactic treatmentof those at risk of developing a disease, such as a cancer, for example.

[0247] The phrase “therapeutically-effective” is intended to qualify theamount of each agent, which will achieve the goal of improvement indisorder severity and the frequency of incidence over treatment of eachagent by itself, while avoiding adverse side effects typicallyassociated with alternative therapies. For example, effectiveneuroplastic therapeutic agents prolong the survivability of thepatient, inhibit the rapidly-proliferating cell growth associated withthe neoplasm, or effect a regression of the neoplasm. Alternatively,effective therapeutic agents for the treatment of neurological disordersminimize the damage from injury, improve cognitive functions, and thelike.

[0248] The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

[0249] Where the term “alkyl” is used, either alone or within otherterms such as “haloalkyl” and “alkylamino”, it embraces linear orbranched radicals having one to about twenty carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkylradicals are “lower alkyl” radicals having one to about six carbonatoms. Examples of such radicals include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl and the like. Even more preferred are lower alkyl radicals havingone to four carbon atoms. The term “alkylenyl” embraces bridgingdivalent alkyl radicals such as methylenyl and ethyleneyl.

[0250] The term “alkenyl” embraces linear or branched radicals having atleast one carbon-carbon double bond of two to about twenty carbon atomsor, preferably, two to about twelve carbon atoms. More preferred alkenylradicals are “lower alkenyl” radicals having two to about four carbonatoms. Examples of alkenyl radicals include ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “loweralkenyl”, embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations.

[0251] The term “alkynyl” denotes linear or branched radicals having twoto about twenty carbon atoms or, preferably, two to about twelve carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about ten carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, butynyl, and the like.

[0252] The term “halo” means halogens such as fluorine, chlorine,bromine or iodine atoms.

[0253] The term “haloalkyl” embraces radicals wherein any one or more ofthe alkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals. A monohaloalkyl radical, for one example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of tie same halo atoms or acombination of different halo radicals. “Lower haloalkyl” embracesradicals having 1-6 carbon atoms. Even more preferred are lowerhaloalkyl radicals having one to three carbon atoms. Examples ofhaloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Perfluoroalkyl” means alkyl radicals having allhydrogen atoms replaced with fluoro atoms. Examples includetrifluoromethyl and pentafluoroethyl.

[0254] The term “hydroxyalkyl” embraces linear or branched alkylradicals having one to about ten carbon atoms any one of which may besubstituted with one or more hydroxyl radicals. More preferredhydroxyalkyl radicals are “lower hydroxyalkyl” radicals having one tosix carbon atoms and one or more hydroxyl radicals. Examples of suchradicals include hydroxymethyl, hydroxyethyl, hydroxypropyl,hydroxybutyl and hydroxyhexyl. Even more preferred are lowerhydroxyalkyl radicals having one to three carbon atoms.

[0255] The term “azidoalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more azido (N₃) radicals. More preferred azidoalkyl radicalsare “lower azidoalkyl” radicals having one to six carbon atoms and oneazido radical. Examples of such radicals include azidomethyl. Even morepreferred are lower azidoalkyl radicals having one to three carbonatoms.

[0256] The term “cyanoalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more cyano (CN) radicals. More preferred cyanoalkyl radicalsare “lower cyanoalkyl” radicals having one to six carbon atoms and onecyano radical. Examples of such radicals include cyanomethyl. Even morepreferred are lower cyanoalkyl radicals having one to three carbonatoms.

[0257] The term “phenyloxyalkyl” embraces linear or branched alkylradicals having one to about ten carbon atoms any one of which may besubstituted with one or more phenoxy radicals. More preferredphenyloxyalkyl radicals are “lower phenyloxyalkyl” radicals having oneto six carbon atoms and one phenoxy radical. Examples of such radicalsinclude phenoxymethyl.

[0258] The term “alkoxy” embrace linear or branched oxy-containingradicals each having alkyl portions of one to about ten carbon atoms.More preferred alkoxy radicals are “lower alkoxy” radicals having one tosix carbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. The “alkoxy” radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

[0259] The term “alkoxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more alkoxy radicals. More preferred alkoxyalkyl radicalsare “lower alkoxyalkyl” radicals having one to six carbon atoms and onealkoxy radical. Examples of such radicals include methoxymethyl.

[0260] The term “aminoalkoxyalkyl” embraces alkoxyalkyl radicals, asdefined above, where any one carbon atom may be substituted with oneamino radical. More preferred aminoalkoxyalkyl radicals are “loweraminoalkoxyalkyl” radicals having one to six carbon atoms. Examples ofsuch radicals include aminoethoxymethyl.

[0261] The term “alkylaminoalkoxy” embraces alkoxy radicals, as definedabove, substituted with an alkylamino radical. More preferredalkylaminoalkoxy radicals are “lower alkylaminoalkoxy” radicals havingalkoxy groups with one to six carbon atoms and an alkylamino radicalwith one to six carbon atoms. Examples of such radicals includemethylaminomethoxy.

[0262] The term “aryl”, alone or in combination, means a carbocyclicaromatic system containing one or two rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl. More preferred aryl is phenyl. Said “aryl” groupmay have 1 to 3 substituents such as lower alkyl, hydroxyl, halo,haloalkyl, nitro, cyano, alkoxy and lower alkylamino.

[0263] The term “heterocyclyl” embraces saturated, partially saturatedand unsaturated heteroatom-containing ring-shaped radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. It doesnot include rings containing —O—O—,—O—S— or —S—S— portions. Said“heterocyclyl” group may have 1 to 3 substituents such as BOC, hydroxyl,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

[0264] Examples of saturated heterocyclic radicals include saturated 3to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms[e.g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl]; saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturatedheterocyclyl radicals include dihydrothiophene, dihydropyran,dihydrofuran and dihydrothiazole.

[0265] Examples of unsaturated heterocyclic radicals, also termed“heteroaryl” radicals, include unsaturated 5 to 6 memberedheteromonocyclyl group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated3 to 6-membered heteromonocyclic group containing an oxygen atom, forexample, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-memberedheteromonocyclic group containing a sulfur atom, for example, 2-thienyl,3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example,oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

[0266] The term also embraces radicals where heterocyclic radicals arefused/condensed with aryl radicals: unsaturated condensed heterocyclicgroup containing 1 to 5 nitrogen atoms, for example, indolyl,isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl,benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl,benzothiadiazolyl].

[0267] The term also includes bridged, spiro and oxo-containingheterocyclic rings, such as 1,4-dioxa-8-aza-spiro[4.5]decyl,phthalimidyl, 1,4-dioxa-8-aza-spiro[4.5]decyl, and(1-aza-bicyclo[2.2.2]oct-3-yl).

[0268] Preferred heterocyclic radicals include five to ten memberedfused or unfused radicals. More preferred examples of heteroarylradicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl,thiazolyl, oxazolyl, furyl, and pyrazinyl. Even more preferredheteroaryl radicals are 5- or 6-membered heteroaryl, containing one ortwo heteroatoms selected from sulfur nitrogen and oxygen, selected fromthienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

[0269] The term “sulfonyl”, whether used alone or linked to other termssuch as alkylsulfonyl, denotes respectively divalent radicals —SO₂—.

[0270] The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” whetheralone or used with terms such as “N-alkylaminosulfonyl”,“N-arylaminosulfonyl”, “N,N-dialkylaminosulfonyl” and“N-alkyl-N-arylaminosulfonyl”, denotes a sulfonyl radical substitutedwith an amine radical, forming a sulfonamide (—SO₂NH₂).

[0271] The term “alkylaminosulfonyl” includes “Nalkylaminosulfonyl” and“N,N-dialkylaminosulfonyl” where sulfamyl radicals are substituted,respectively, with one alkyl radical, or two alkyl radicals. Morepreferred alkylaminosulfonyl radicals are “lower alkylaminosulfonyl”radicals having one to six carbon atoms. Even more preferred are loweralkylaminosulfonyl radicals having one to three carbon atoms. Examplesof such lower alkylaminosulfonyl radicals include N-methylaminosulfonyl,N-ethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl.

[0272] The terms “N-arylaminosulfonyl” and “N-alkyl-Narylaminosulfonyl”denote sulfamyl radicals substituted, respectively, with one arylradical, or one alkyl and one aryl radical. More preferredN-alkyl-N-arylaminosulfonyl radicals are “lower N-alkyl-N-arylsulfonyl”radicals having alkyl radicals of one to six carbon atoms. Even morepreferred are lower N-alkyl-N-arylsulfonyl radicals having one to threecarbon atoms. Examples of such lower N-alkyl-Naryl-aminosulfonylradicals include N-methyl-N-phenylaminosulfonyl andN-ethyl-N-phenylaminosulfonyl. Examples of such N-aryl-aminosulfonylradicals include N-phenylaminosulfonyl, which may be optionallysubstituted on the phenyl ring.

[0273] The term “arylalkylaminosulfonyl” embraces aralkyl radicals asdescribed above, attached to an aminosulfonyl radical. More preferredare lower arylalkylaminosulfonyl radicals having one to three carbonatoms.

[0274] The term “heterocyclylaminosulfonyl” embraces heterocyclylradicals as described above, attached to an aminosulfonyl radical.

[0275] The term “heterocyclylsulfonylalkyl” embraces heterocyclylradicals as described above, attached to an alkyl radical through asulfonyl linker. More preferred are “lower heterocyclylsulfonylalkyl”wherein the alkyl portion is one to six carbons long. Even morepreferred, the alkyl portions are 1-3 carbons long.

[0276] The terms “carboxy” or “carboxyl”, whether used alone or withother terms, such as “carboxyalkyl”, denotes —CO₂H.

[0277] The term “carbonyl”, whether used alone or with other terms, suchas “aminocarbonyl”, denotes —(C═O)—.

[0278] The term “aminocarbonyl” when used by itself or with other termssuch as “aminocarbonylalkyl”, “Nalkylaminocarbonyl”,“N-arylaminocarbonyl”, “N,N-dialkylaminocarbonyl”,“N-alkyl-N-arylaminocarbonyl”, “Nalkyl-N-hydroxyaminocarbonyl” and“N-alkyl-N-hydroxyaminocarbonylalkyl”, denotes an amide group of theformula —C(=O)NH₂.

[0279] The term “alkoxycarbonyl” denotes an ester group wherein thecarbonyl group is substituted with an alkoxy radical, as describedabove. The carbonyl portion is the point of attachment. More preferredare “lower alkoxycarbonyl” having lower alkoxy radicals as describedabove attached to a carbonyl radical.

[0280] The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl”denote aminocarbonyl radicals which have been substituted with one alkylradical and with two alkyl radicals, respectively. More preferred are“lower alkylaminocarbonyl” having lower alkyl radicals as describedabove attached to an aminocarbonyl radical.

[0281] The term “alkylamino-alkylaminocarbonyl”, denotesalkylaminocarbonyl radicals which have been substituted with analkylamino radical. More preferred are “loweralkylamino-alkylaminocarbonyl” having lower alkyl radicals, as describedabove.

[0282] The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl”denote aminocarbonyl radicals substituted, respectively, with one arylradical, or one alkyl and one aryl radical.

[0283] The term “heterocyclylalkylaminocarbonyl” denotes aminocarbonylradicals substituted with a heterocyclylalkyl radical.

[0284] The term “heterocyclylcarbonyl” denotes carbonyl radicalssubstituted with a heterocyclyl radical.

[0285] The term “aminoalkyl” embraces alkyl radicals substituted withamino radicals.

[0286] The term “alkylaminothiocarbonyl” denotes thioamide compoundscomprising thiocarbonyl radicals (—C(S)—) which have been substitutedwith an alkylamino radicals. More preferred are “loweralkylaminothiocarbonyl” having lower alkyl radicals as described above.

[0287] The term “alkylaminoalkyl” embraces aminoalkyl radicals havingthe nitrogen atom substituted with an alkyl radical. The term includesboth mono- and di-substituted amines. Even more preferred are loweralkylaminoalkyl radicals having one to three carbon atoms.

[0288] The term “heterocyclylalkyl” embraces heterocyclic-substitutedalkyl radicals. More preferred heterocyclylalkyl radicals are “5- or6-membered heteroarylalkyl” radicals having alkyl portions of one to sixcarbon atoms and a 5- or 6-membered heteroaryl radical. Even morepreferred are lower heteroarylalkyl radicals having alkyl portions ofone to three carbon atoms. Examples include such radicals aspyridylmethyl and thienylmethyl.

[0289] The term “aralkyl” embraces aryl-substituted alkyl radicals.Preferable aralkyl radicals are “lower aralkyl” radicals having arylradicals attached to alkyl radicals having one to six carbon atoms. Evenmore preferred are lower aralkyl radicals phenyl attached to alkylportions having one to three carbon atoms. Examples of such radicalsinclude benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkylmay be additionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

[0290] The term “arylalkenyl”, embraces aryl-substituted alkenylradicals. Preferable arylalkenyl radicals are “lower arylalkenyl”radicals having aryl radicals attached to alkenyl radicals having two tosix carbon atoms. Examples of such radicals include phenylethenyl. Thearyl in said arylalkenyl may be additionally substituted with halo,alkyl, alkoxy, halkoalkyl and haloalkoxy.

[0291] The term “arylalkynyl” embraces aryl-substituted alkynylradicals. Preferable arylalkynyl radicals are “lower arylalkynyl”radicals having aryl radicals attached to alkynyl radicals having two tosix carbon atoms. Examples of such radicals include phenylethynyl. Thearyl in said aralkyl may be additionally substituted with halo, alkyl,alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl areinterchangeable.

[0292] The term “alkylthio” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, attached to adivalent sulfur atom. Even more preferred are lower alkylthio radicalshaving one to three carbon atoms. An example of “alkylthio” ismethylthio, (CH₃S—).

[0293] The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

[0294] The term “alkylsulfinyl” embraces radicals containing a linear orbranched alkyl radical, of one to ten carbon atoms, attached to adivalent —S(═O)— atom. More preferred are lower alkylsulfinyl radicalshaving one to three carbon atoms.

[0295] The term “arylsulfinyl” embraces radicals containing an arylradical, attached to a divalent —S(═O)— atom. Even more preferred areoptionally substituted phenylsulfinyl radicals.

[0296] The term “haloalkylsulfinyl” embraces radicals containing ahaloalkyl radical, of one to ten carbon atoms, attached to a divalent—S(═O)— atom. Even more preferred are lower haloalkylsulfinyl radicalshaving one to three carbon atoms.

[0297] The term “alkylamino” denotes amino groups which have beensubstituted with one alkyl radical and with two alkyl radicals,including terms “N-alkylamino” and “N,N-dialkylamino”. More preferredalkylamino radicals are “lower alkylaminol” radicals having one or twoalkyl radicals of one to six carbon atoms, attached to a nitrogen atom.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Suitable “alkylamino” may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or thelike.

[0298] The term “hydroxyalkylamino” denotes amino groups which have beensubstituted with a hydroxyalkyl radical, as defined above.

[0299] The term “heterocyclylalkylamino” denotes alkylamino groups whichhave been substituted with a heterocyclyl radical, as defined above.

[0300] The tern “arylamino” denotes amino groups which have beensubstituted with one or two aryl radicals, such as N-phenylamino. The“arylamino” radicals may be further substituted on the aryl ring portionof the radical.

[0301] The term “heteroarylamino” denotes amino groups which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

[0302] The term “aralkylamino” denotes amino groups which have beensubstituted with one or two aralkyl radicals. More preferred arephenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. The“aralkylamino” radicals may be further substituted on the aryl ringportion of the radical.

[0303] The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino”denote amino groups which have been substituted with one aralkyl and onealkyl radical, or one aryl and one alkyl radical, respectively, to anamino group.

[0304] The term “arylthio” embraces aryl radicals of six to ten carbonatoms, attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

[0305] The term “aralkylthio” embraces aralkyl radicals as describedabove, attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

[0306] The term “aryloxy” embraces optionally substituted aryl radicals,as defined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

[0307] The term “heterocyclyloxy” embraces optionally substitutedheterocyclyl radicals, as defined above, attached to an oxygen atom.Examples of such radicals include pyrrolidinyloxy, piperidinyloxy, andpyridyloxy.

[0308] The term “aralkoxy” embraces oxy-containing aralkyl radicalsattached through an oxygen atom to other radicals. More preferredaralkoxy radicals are “lower aralkoxy” radicals having optionallysubstituted phenyl radicals attached to lower alkoxy radical asdescribed above.

[0309] The term “heterocyclylalkoxy” embraces oxy-containingheterocyclylalkyl radicals attached through an oxygen atom to otherradicals. More preferred heterocyclyloxy radicals are “lowerheterocyclyloxy “radicals having optionally substituted 5-6 memberedheterocyclyl radicals attached to lower alkoxy radical as describedabove.

[0310] The term “cycloalkyl” includes saturated carbocyclic groups.Preferred cycloalkyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopropyl, cyclopentyl and cyclohexyl.

[0311] The term “cycloalkenyl” includes carbocyclic groups having one ormore carbon-carbon double bonds. “Cycloalkenyl” and “cycloalkyldienyl”compounds are included. Preferred cycloalkenyl groups include C₃-C₆rings. More preferred compounds include, for example, cyclopentenyl,cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

[0312] The term “comprising” is meant to be open ended, including theindicated component but not excluding other elements.

[0313] The present invention preferably includes compounds thatselectively inhibit GSK, CDK2 and/or CDK5.

[0314] The present invention also comprises the use of a compound of theinvention, or pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment either acutely orchronically of a cell proliferation or apoptosis mediated disease state,including those described previously. The compounds of the presentinvention are also useful in the manufacture of an anti-cancermedicament. The compounds of the present invention are also useful inthe manufacture of a medicament to attenuate or prevent disordersthrough inhibition of CDKs and other kinases. The compounds of thepresent invention are also useful in the manufacture of a medicament totreat neurological disorders.

[0315] The present invention comprises a pharmaceutical compositioncomprising a therapeutically-effective amount of a compound of FormulasI-VI in association with a least one pharmaceutically-acceptablecarrier, adjuvant or diluent.

[0316] The present invention also comprises a method of treating cellproliferative disorders, apoptosis mediated disorders, cancer, CDKmediated disorder or neurological disorders, in a subject, the methodcomprising treating the subject having or susceptible to such disorderwith a therapeutically-effective amount of a compound of Formulas I-VI.

[0317] Combinations

[0318] While the compounds of the invention can be administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or other agents. Whenadministered as a combination, the therapeutic agents can be formulatedas separate compositions that are administered at the same time orsequentially at different times, or the therapeutic agents can be givenas a single composition. The phrase “co-therapy” (or“combination-therapy”), in defining use of a compound of the presentinvention and another pharmaceutical agent, is intended to embraceadministration of each agent in a sequential manner in a regimen thatwill provide beneficial effects of the drug combination, and is intendedas well to embrace co-administration of these agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofthese active agents or in multiple, separate capsules for each agent.

[0319] Specifically, the administration of compounds of the presentinvention may be in conjunction with additional therapies known to thoseskilled in the art in the treatment of neoplasia, such as with radiationtherapy or with cytostatic or cytotoxic agents; or in the treatment ofneurological disorders, such as with thrombolytic and anticoagulantagents, anti-inflammatory agents, NMDA inhibitors, antiparkinsonianagents, and inhibitors of lipid peroxidation.

[0320] If formulated as a fixed dose, such combination products employthe compounds of this invention within the accepted dosage ranges.Compounds of Formula I-VI may also be administered sequentially withknown agents when a combination formulation is inappropriate. Theinvention is not limited in the sequence of administration; compounds ofthe invention may be administered either prior to, at the same time withor after administration of the other agent.

[0321] Currently, standard treatment of primary tumors consists ofsurgical excision followed by either radiation or IV administeredchemotherapy. The typical chemotherapy regime consists of either DNAalkylating agents, DNA intercalating agents or microtubule poisons. Thechemotherapy doses used are just below the maximal tolerated dose andtherefore dose limiting toxicities typically include, nausea, vomiting,diarrhea, hair loss, neutropenia and the like. Experiments performed inin vivo animal models and in in vitro cell based assays havedemonstrated that combining chemotherapeutic agents with cell cycleinhibitors, such as CDK inhibitors, typically results in eitherdecreased rate of tumor growth or, in some cases, tumor regression.Combining chemotherapy with a CDK inhibitor typically results in anincreased therapeutic index and lower levels of both agents arerequired. This ultimately results in a decrease in toxicity and anincrease in efficacy.

[0322] Schwartz et al, Clin. Can. Res., 3,1467-1472 (1997) havedemonstrated that combining the CDK inhibitor flavopiridol withmitomycin-C (DNA alkylating agent) resulted in an increased rate ofapoptosis in gastric and breast cancer cells. Bible et al (Bible et al.,Cancer Res., 57, 3375-3380 (1997) have also demonstrated therapeuticsynergy exists between flavopiridol and paclitaxel, cytarabine,topotecan, doxorubicin, and etoposide (all standard chemotherapeuticagents) when tested in cell based assays using human non-small cell lungcancer cells. Preclinical models (cell culture) suggest that a cellcycle inhibitor potentiates the effect of a cytotoxic agent whenadministered after the chemotherapeutic agent. The chemotherapeuticagent will induce specific DNA/mitotic damage checkpoints in normalcells which in combination with a CDK inhibitor will cause a cell cyclearrest or cytostatic effect. In contrast, tumor cells will be driveninto apoptosis or cell death when a chemotherapeutic agent and a CDKinhibitor are combined due to tumor cells attempting to activatedefective DNA damage and cell cycle checkpoints. In addition, schedulingof a CDK inhibitor for clinical trials should include a rest period toallow the patients normal cells to recover and reduce the potential forcytotoxic side effects.

[0323] There are large numbers of antineoplastic agents available incommercial use, in clinical evaluation and in pre-clinical development,which would be selected for treatment of neoplasia by combination drugchemotherapy. Such antineoplastic agents fall into several majorcategories, namely, antibiotic-type agents, alkylating agents,antimetabolite agents, hormonal agents, immunological agents,interferon-type agents and a category of miscellaneous agents.

[0324] A first family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantimetabolite-type/thymidilate synthase inhibitor antineoplasticagents. Suitable antimetabolite antineoplastic agents may be selectedfrom but not limited to the group consisting of 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,Ciba-Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphatestearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil,N-(2′-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrrolizine, Lilly LY-188011, Lilly LY-264618, methobenzaprim,methotrexate, Wellcome MZPES, norspermidine, NCI NSC-127716, NCINSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA,pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, TakedaTAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, tyrosineprotein kinase inhibitors, Taiho UFT and uricytin.

[0325] A second family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofalkylating-type antineoplastic agents. Suitable alkylating-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Shionogi 254-S, aldo-phosphamide analogues, altretamine,anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane,Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153,chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558,Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP(Myr)2,diphenylspiromustine, diplatinum cytostatic, Erba distamycinderivatives, Chugai DWA-2114R, ITI E09, elmustine, Erbamont FCE-24517,estramustine phosphate sodium, fotemustine, Unimed G-6-M, ChinoinGYKI-17230, hepsul-fam, ifosfamide, iproplatin, lomustine, mafosfamide,mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215,oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine,semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tine,Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone,tetraplatin and trimelamol.

[0326] A third family of antineoplastic agents which may be used incombination with compounds of the present invention consists ofantibiotic-type antineoplastic agents. Suitable antibiotic-typeantineoplastic agents may be selected from but not limited to the groupconsisting of Taiho 4181-A, aclarubicin, actinomycin D, actinoplanone,Erbamont ADR-456, aeroplysinin derivative, Ajinomoto AN-201-II,Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A,bisucaberin, Bristol-Myers BL-6859, Bristol-Myers BMY-25067,Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-MyersBMY-27557, Bristol-Myers BMY-28438, bleomycin sulfate, bryostatin-1,Taiho C-1027, calichemycin, chromoximycin, dactinomycin, daunorubicin,Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa HakkoDC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41,doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin,esorubicin, esperamicin-A1, esperamicin-A1b, Erbamont FCE-21954,Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin,gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin,kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa HakkoKT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American CyanamidLL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone,SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, Nippon KayakuNKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

[0327] A fourth family of antineoplastic agents which may be used incombination with compounds of the present invention consists of amiscellaneous family of antineoplastic agents, including tubulininteracting agents, topoisomerase II inhibitors, topoisomerase Iinhibitors and hormonal agents, selected from but not limited to thegroup consisting of α-carotene, α-difluoromethyl-arginine, acitretin,Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile,amsacrine, Angiostat, ankinomycin, anti-neoplaston A10, antineoplastonA2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, HenkelAPD, aphidicolin glycinate, asparaginase, Avarol, baccharin, batracylin,benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisantrene,Bristol-Myers BMY-40481, Vestar boron-10, bromofosfamide, WellcomeBW-502, Wellcome BW-773, caracemide, carmethizole hydrochloride,Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX-100,Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941,Warner-Lambert CI-958, clanfenur, claviridenone, ICN compound 1259, ICNcompound 4711, Contracan, Yakult Honsha CPT-II, crisnatol, curaderm,cytochalasin B. cytarabine, cytocytin, Merz D-609, DABIS maleate,dacarbazine, datelliptinium, didemnin-B, dihaematoporphyrin ether,dihydrolenperone, dinaline, distamycin, Toyo Pharmar DM-341, ToyoPharmar DM-75, Daiichi Seiyaku DN-9693, docetaxel elliprabin,elliptinium acetate, Tsumura EPMTC, the epothilones, ergotamine,etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate,genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolan NMF-5N,hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanlne derivatives,methylanilinoacridine, Molecular Genetics MGI-A-706B 136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707,Warner-Lambert PD-115934, Warner-Lambert PD-131141, Pierre FabrePE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreicacid, Efamol porphyrin, probimane, procarbazine, proglumide, Invitronprotease nexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS,restrictin-P, retelliptine, retinoic acid, Rhone-Poulenc RP-49532,Rhone-Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo SM-108, KuraraySMANCS, SeaPharm SP-10094, spatol, spirocyclopropane derivatives,spirogermanium, Unimed, SS Pharmaceutical SS-554, strypoldinone,Stypoldione, Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase,Toyama T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide,thaliblastine, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin,Teijin TT-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, ukrain, EastmanKodak USB-006, vinblastine sulfate, vincristine, vindesine,vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides andYamanouchi YM-534.

[0328] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as acemannan,aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine,amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide,anastrozole, ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002(Novelos), bexarotene, bicalutamide, broxuridine, capecitabine,celecoxib, celmoleukin, cetrorelix, cladribine, clotrimazole, cytarabineocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox,deslorelin, dexrazoxane, dilazep, docetaxel, docosanol, doxercalciferol,doxifluridine, doxorubicin, bromocriptine, carmustine, cytarabine,fluorouracil, HIT diclofenac, interferon alfa, daunorubicin,doxorubicin, tretinoin, edelfosine, edrecolomab, eflornithine, emitefur,epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, gemtuzumab zogamicin,gimeracil/oteracil/tegafur combination, glycopine, goserelin,heptaplatin, human chorionic gonadotropin, human fetal alphafetoprotein, ibandronic acid, idarubicin, (imiquimod, interferon alfa,interferon alfa, natural, interferon alfa-2, interferon alfa-2a,interferon alfa-2b, interferon alfa-N1, interferon alfa-n3, interferonalfacon-1, interferon alpha, natural, interferon beta, interferonbeta-la, interferon beta-1b, interferon gamma, natural interferongamma-1a, interferon gamma-1b, interleukin-1 beta, iobenguane,irinotecan, irsogladine, lanreotide, LC 9018 (Yakult), leflunomide,lenograstim, lentinan sulfate, letrozole, leukocyte alpha interferon,leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin, lonidamine,lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone,miltefosine, mirimostim, mismatched double stranded RNA, mitoguazone,mitolactol, mitoxantrone, molgramostim, nafarelin, naloxone+pentazocine,nartograstim, nedaplatin, nilutamide, noscapine, novel erythropoiesisstimulating protein, NSC 631570 octreotide, oprelvekin, osaterone,oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferonalfa-2b, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, rabbit antithymocyte polyclonal antibody, polyethyleneglycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed,rasburicase, rhenium Re 186 etidronate, RII retinamide, rituximab,romurtide, samarium (153 Sm) lexidronam, sargramostim, sizofiran,sobuzoxane, sonermin, strontium-89 chloride, suramin, tasonermin,tazarotene, tegafur, temoporfin, temozolomide, teniposide,tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa,topotecan, toremifene, tositumomab-iodine 131, trastuzumab, treosulfan,tretinoin, trilostane, trimetrexate, triptorelin, tumor necrosis factoralpha, natural, ubenimex, bladder cancer vaccine, Maruyama vaccine,melanoma lysate vaccine, valrubicin, verteporfin, vinorelbine,VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941(Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC8015 (Dendreon), cetuximab, decitabine, dexaminoglutethimide,diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil,etanidazole, fenretinide, filgrastim SD01 (Amgen), fulvestrant,galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical),granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab,CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development),HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology),idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb (Techniclone),polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), marimastat,menogaril, mitumomab, motexafin gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA077 (Tanabe), tetrathiomolybdate, thaliblastine, thrombopoietin, tinethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanomavaccine (New York University), melanoma vaccine (Sloan KetteringInstitute), melanoma oncolysate vaccine (New York Medical College),viral melanoma cell lysates vaccine (Royal Newcastle Hospital), orvalspodar.

[0329] Alternatively, the present compounds may also be used inco-therapies with other anti-neoplastic agents, such as other kinaseinhibitors including KDR inhibitors, p38 inhibitors, TNF inhibitors,metallomatrix proteases inhibitors (MMP), COX-2 inhibitors, NSAID's, SODmimics or α_(v)β₃ inhibitors.

[0330] Alternatively, the present compounds may also be used inco-therapies with other treatments for neurological treatments such asthrombolytic and anticoagulant agents including tPA, urokinase andinhibitors of platelet aggregation, p38 inhibitors, ILlra, NMDAinhibitors, antiparkinsonian agents including carbidopa and levodopa,and inhibitors of lipid peroxidation, for example.

[0331] The present invention comprises a process for the preparation ofa compound of Formula I-VI.

[0332] Compounds of the present invention can possess, in general, oneor more asymmetric carbon atoms and are thus capable of existing in theform of optical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

[0333] Compounds of the present invention can possess, in general,tautomeric forms, which are included in the family of compounds inFormula I-VI. Also included in the family of compounds of Formula I-VIare the pharmaceutically-acceptable salts thereof. The termpharmaceutically-acceptable salts, embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. The nature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable acidaddition salts of compounds of Formula I-VI may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuricand phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, example of which areformic, acetic, adipic, butyric, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic,cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic,β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI-VI include metallic salts, such as salts made from aluminum, calcium,lithium, magnesium, potassium, sodium and zinc, or salts made fromorganic bases including primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, trimethylamine. All of these salts may be prepared byconventional means from the corresponding compound of the invention byreacting, for example, the appropriate acid or base with the compound ofFormula I-VI.

[0334] Also, the basic nitrogen-containing groups can be quaternizedwith such agents as lower alkyl halides, such as methyl, ethyl, propyl,and butyl chloride, bromides and iodides; dialkyl sulfates likedimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides,aralkyl halides like benzyl and phenethyl bromides, and others. Water oroil-soluble or dispersible products are thereby obtained.

[0335] Examples of acids that may be employed to from pharmaceuticallyacceptable acid addition salts include such inorganic acids as HCl,H₂SO₄ and H₃PO₄ and such organic acids as oxalic acid, maleic acid,succinic acid and citric acid. Other examples include salts with alkalimetals or alkaline earth metals, such as sodium, potassium, calcium ormagnesium or with organic bases.

[0336] Additional examples of such salts can be found in Berge et al.,J. Pharm. Sci., 66, 1 (1977).

[0337] General Synthetic Procedures

[0338] The compounds of the invention can be synthesized according tothe following procedures of Schemes 1-24, wherein the substituents areas defined for Formulas I-VI, above, except where further noted.

[0339] Substituted pyridines can be prepared according to the method setout in Scheme 1. A mixture of halo-aniline 1, substituted amine andphenol is reacted, preferably at a temperature above RT and morepreferably at temperature of about 150° C., to yield the heterocyclylderivative 2a or substituted amine derivative 2b.

[0340] Substituted pyridines can be prepared according to the method setout in Scheme 2. A halopicolinic acid 3 is reacted with substitutedamines (where R^(a) and R^(b) are H, alkyl, substituted alkyl, etc.) inthe presence of chloroformate esters and base in a suitable solvent toform the halopyridyl amide derivatives 4. Preferably the reaction is ata temperature below RT, more preferably the reaction occurs at atemperature of about 0° C. The halopyridyl amide 4 is dehalogenated,such as with NH₄OH and Cu powder in an appropriate solvent, such as IpOHto form the aniline derivative 5. Preferably the reaction occurs at atemperature above RT, more preferably the reaction occurs at about 100°C. The aniline derivative 5 is reduced, such as with LiAlH₄ in Et₂O toform the aminoalkyl derivative 6.

[0341] Substituted 4-thiazolylurea compounds 12 are prepared from thecorresponding nitriles 7 according to the method set out in Scheme 3.Substituted nitriles 7 are added to base at about RT and H₂S is bubbledthrough the solution, to yield the thione 8. The thione 8 is combinedwith ethyl bromopyruvate and heated to form the thiazolyl carboxylateester 9. Aqueous LiOH is heated with the ester 9 at a temperature aboveRT and preferably at reflux to give the thiazole carboxylic acid 10.Treatment of the substituted thiazolyl carboxylic acid 10 with base in asuitable solvent at about RT yields a salt. At about 0° C., oxalylchloride is added to a suspension of the salt in solvent followed by acatalytic amount of DMF. Afterwards, aqueous NaN₃ is added to yield thethiazolyl carbonyl azide 11. The carbonyl azide 11 is added tosubstituted amines to form the thiazolyl urea compound 12.

[0342] Substituted 4-thiazolylurea compounds 12 are prepared from eitherthe corresponding nitriles 7a or the corresponding amides 7b accordingto the method set out in Scheme 3. Substituted nitriles 7a are added tobase at about RT and H₂S is bubbled through the solution, to yield thethione 8. Alternatively, substituted amides 7b are treated with P₂S₅,NaCO₃ in THF and heated to give 8. The thione 8 is combined with ethylbromopyruvate and heated to form the thiazolyl carboxylate ester 9.Aqueous LiOH is heated with the ester 9 at a temperature above RT andpreferably at reflux to give the thiazole carboxylic acid 10. Treatmentof the substituted thiazolyl carboxylic acid 10 with base in a suitablesolvent at about RT yields a salt. At about 0° C., oxalyl chloride isadded to a suspension of the salt in solvent followed by a catalyticamount of DMF. Afterwards, aqueous NaN₃ is added to yield the thiazolylcarbonyl azide 11. The carbonyl azide 11 is added to substituted aminesto form the thiazolyl urea compound 12.

[0343] Substituted 4-thiazolylurea compounds 27 are prepared from thecorresponding pyridines 24 according to the method set out in Scheme 58.Reductive amination with an amine (including nitrogen-containingheterocycles) and 6-bromo-2-pyridinecarboxaldehyde 24, is achieved suchas in a halocarbon solvent such as dichloromethane, in the presence ofNaBH(OAc)₃ and acid, such as AcOH, to give2-aminomethyl-6-bromo-pyridine 25. The 2-aminomethyl-6-bromo-pyridine 25is aminated, such as with NH₄OH in the presence of Cu powder, such as inthe presence of an alcohol solvent, at a temperature above about 50° C.and preferably at about 100° C, such as in a sealed tube to give thecorresponding aniline 6. A substituted thiazolylcarbonylazide, such asin dry hydrocarbon solvent such as toluene is heated at a temperatureabove about 50° C. and preferably above about 85° C. and reacted withthe aniline 6 to give the 4-thiazolylurea compounds 27.

[0344] Alternatively, the aniline 6 can be coupled with thiazolylcarboxylic acid, such as with DPPA in the presence of base, such as TEA,and molecular sieves in a solvent like THF. The reaction can be heatedat a temperature above about 50° C. and preferably at about refluxyielding the 4thiazolylurea compounds 27.

[0345] Thiazolyl carboxylic acid 31 (especially appropriate where R′ isa sulfonamide or amine) are prepared from the correspondingbenzonitriles 28 as described in Scheme 9. H₂S is added to thesubstituted 4-cyanobenzene 28 in the presence of base, such as Et₃N toafford the thiobenzamide 29. The thiobenzamide 29 is reacted with ethylbromopyruvate, such as in an alcohol solvent like EtOH, at a temperaturegreater than about 50° C., and preferably at about 75° C. to give thethiazolyl ester 30. The thiazolyl ester 30 is hydrolyzed, such as withLiOH monohydrate in an alcohol like aqueous MeOH, at a temperaturegreater than about 50° C., and preferably at about 75° C., to providethe acid 31. The acid can be used similar to that described in Scheme 8.

[0346] Substituted anilines 35 are prepared from the correspondingmethyl compounds 32 as described in Scheme 10. 2-Amino-3-picoline isprotected such as with solid carboethoxyphthalimide and base like TEA toprovide the phthalimide (Phth) protected aniline 32. The protected3-methylaniline is brominated, such as with NBS and AIBN at atemperature above 50° C. and preferably at about reflux. Additional AIBNand NBS may be needed to push the reaction to completeness. Thedibromomethyl aniline 34 is reacted with an amine, preferably asecondary amine such as substituted or unsubstituted nitrogen containingheterocyclics like piperidines and piperazines, in the presence of acidlike glacial AcOH and halocarbon solvent such as CH₂Cl₂. Treatment withNaBH(OAc)₃ provided the protected substituted methyl compound which isdeported, such as by treatment with hydrazine monohydrate at atemperature greater than about 50° C., and preferably at reflux toprovide the substituted aniline 35.

[0347] Substituted anilines 39 are prepared from the correspondingmethyl compounds 36 as described in Scheme 11.N-Pivaloyl-2-amino-6-bromomethylpyridine 37 is prepared by the method ofM. V. Papadopoulou, et al. (J. Heterocyclic Chem., 1995, 32, 675-681).The protected bromomethyl compound is treated with an alcohol or aminein the presence of base, such as NaH to yield the corresponding ether oramino alkyl compounds 38 (where X is O or N). The protected ether oramino alkyl compounds 38 is treated with base, such as in methanolic KOHand warmed to a temperature greater than about RT, and preferably atabout 55° C., to provide the substituted anilines 39.

[0348] Thiazolylcarbonylazides 43 are prepared as described in Scheme12. Bromothiazole is coupled with an aryl alcohol, such as phenol, at atemperature greater than about 100° C., and preferably at about 180° C.,to provide the phenoxy compound 41. The thiazolyl ester 41 ishydrolyzed, such as with LiOH monohydrate in an alcohol like aqueousMeOH, at a temperature greater than about 50° C., and preferably atabout 75° C., to provide the acid 42. Acid 42 is added to ethylchloroformate and NaN₃, in the presence of base such as TEA, to providethe azide 43, which can be used as described in Scheme 8.

[0349] Pyridyl-2-thiazoles 47 are prepared as described in Scheme 13.4-Chloronicotinamide 44 is converted to the thioamide 45 such as betreatment with P₂S₅, in the presence of base, such as Na₂CO₃, at atemperature greater than about 50° C., and preferably at about reflux.The thioamide 45 is converted to the thiazole ester 46 by treatment withbromoethylpyruvate and heating at a temperature greater than about 50°C., and preferably at about reflux. The ethyl ester is transesterifiedto the methyl ester with treatment with base, such as NaOMe. Furtheraddition of base and heating at a temperature greater than about 50° C.,and preferably at about reflux, hydrolyzed the ester to the acid.Additional NaOMe, in the presence of MeOH, and heating at a temperaturegreater than about 50° C., and preferably at about reflux, provided themethoxy substituted pyridine compound 47. Use of other bases andalcohols provide alternative alkoxy substituted compounds.

[0350] Protected aminoalkyl pyridines 53 are prepared from the2-amino-6-methylpyridine 48 as described in Scheme 14.

[0351] The amino group of 2-amino-6-methylpyridine 48 is protected, suchas with BOC and normal coupling chemistry, such as with Boc₂O and base,like TEA, and DMAP. The protected compound 49 is brominated such as withNBS and AIBN and heating at a temperature greater than about 50° C., andpreferably at reflux to provide the bromomethyl derivative 50. Thebromomethyl derivative 50 is converted to the cyanomethyl compound 51such as with treatment with NaCN in the presence of alcohol solvent suchas EtOH, and heating at a temperature greater than about 50° C., andpreferably at reflux. The cyanomethyl compound 51 is hydrogenated to theaminoethyl derivative 52 such as with hydrogen in the presence ofPd(OH)₂/C at a temperature about RT. The aminoethyl derivative 52 isconverted to the di-protected compound such as with phthalic anhydrideand heating at a temperature between RT and about 70° C. Upon treatmentwith strong acid, such as TFA, provides the 2-aminopyridyl compound 53.

[0352] Compounds of Formula I are prepared as described in Scheme 15.Phthalimidylethyl compounds 54 are prepared from the coupling ofcompounds prepared similar to those described in Scheme 14 and thiazolylacylazides as described in Scheme 8. Treatment of 54 with hydrazinehydrate and heating at a temperature greater than about 50° C., andpreferably at reflux, provides the aminoethyl derivatives 55. Alkylationof the amine 55, such as with paraformaldehyde and NaBH(OAc)₃ in ahaloalkyl solvent, such as CH₂Cl₂ provides the dimethylamine 56.

[0353] Compounds of Formula I (where R⁷ is optionally substitutedphenyl) are prepared as described in Scheme 16. The 2-aminothiazole 57is prepared from thiourea and ethyl bromopyruvate, in an alcoholicsolvent like ethanol, at a temperature greater than about RT, andpreferably at about 45° C. Treatment of the ethyl2-aminothiazole-4-carboxylate with HBr, NaNO₂, CuBr and heating at atemperature greater than about 50° C., and preferably at about 70° C.,provides the bromo thiazole ester. Hydrolysis of the ester, such as withaqueous NaOH and alcohol, such as EtOH and heating at a temperaturegreater than about 50° C., and preferably at reflux provides thebromothiazole acid 58. Coupling with substituted amines, similar to thatdescribed in Scheme 8, provides the 2-bromothiazolyl urea 59. Suzukicoupling of 2-bromothiazolyl urea 59 with phenyl boronic acids providesthe compounds where R⁷ is optionally substituted phenyl 60.

[0354] Substituted aminopyridines 65 are prepared by the methoddescribed in Scheme 17. 2-[(6-Bromo-2-pyridyl)methyl]aminopropan-1-ol 61is protected such as with Boc with di-tert-butyldicarbonate in dryCH₂Cl₂. Conversion to the aldehyde 63 is accomplished by treatment withoxalyl chloride (in CH₂Cl₂), and DMSO at a temperature below RT,preferably below about −23° C. and more preferably at about −63° C.Addition of bas,e such as DEA, to the aldehyde 63, and heating to refluxin a Dean-Stark trap, followed by the addition of a solution ofNaBH(OAc)₃ in acid such as AcOH at RT provided the aminoalkyl-aminoalkylderivative 64. The aminopyridine 65 is prepared as described above.

[0355] Substituted aminopyridines 69 are prepared by the methoddescribed in Scheme 18. 2-Chloroisonicotinic acid 66 is coupled with anamine, such as with standard coupling chemistry, for example with acarbodiimide, such as EDCI, in the presence of base, such as DIEA, in anappropriate solvent such as CH₂Cl₂, to provide amide 67 where R^(a) isalkyl, aryl or together with the nitrogen atom forms a heterocyclicring. The nicotinamide is aminated, such as with ammonium hydroxide inthe presence of a metal such as Cu in an appropriate solvent such asIpOH and heated at a temperature above RT, preferably above about 50°C., more preferably at about 100° C., preferably in a sealed tub vessel,to form the amino-nicotinamide 68. The aminonicotinamide 68 is reduced,such as with LAH, at a temperature above RT, preferably above about 50°C., more preferably at about reflux, to form the methylamine 69.

[0356] Substituted alkynyl thiazoles 72 are prepared by the methodoutlined in Scheme 19 where R^(b) is cycloalkyl, alkyl and the like.Bromothiazole 71 is substituted with the alkyne 70, such as in thepresence of Pd(PhCN)₂Cl₂, CuI₂ and t-Bu₃P, and base such as DEA, in anappropriate solvent such as dioxane. The reaction temperature ismaintained at about RT, to form the alkynyl thiazoles 72.

[0357] Thiazolylazides 76 are prepared by the method shown in Scheme 20.2-Amino-thiazole-4-carboxylic acid ester hydrobromide is basified, suchas with a saturated solution of NaHCO₃ to provide the free base. Thefree base is subsequently halogenated, such as with a metal halide,preferably NaCl or NaBr, in the presence of acid, preferably H₂SO₄, morepreferably 9M H₂SO₄, and CuSO₄ and NaNO₂ at a temperature of about RT toform the halothiazole. The 2-halothiazole-4-carboxylic acid ester ishydrolyzed with a base, such as LiOH, at a temperature above RT,preferably above about 50° C., more preferably about 65° C., to formacid 75. The azido-thiazole 76 is prepared from the2-halothiazole-4-carboxylic acid 75 in the presence of base, such asTEA, ethyl chloroformate and sodium azide at a temperature about RT.

[0358] Substituted bromo-pyridines 78 and 79 are prepared fromdibromo-pyridine 77 as described in Scheme 21. 2,6-Dibromopyridine 77 isreacted with an aminoalcohol in an appropriate solvent, such as THF, ata temperature above RT, preferably at a temperature above about 50° C.,more preferably at reflux, to form the amino pyridine. Thealcoholamino-pyridine is coupled with 3,4-dihydro-2H-pyran such as withTsOH in the presence of an appropriate solvent, such as CH₂Cl₂ at atemperature of about RT, to form the pyran substituted pyridine 78.

[0359] D-2-Hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl esteris treated with a strong base, preferably NaH, at a temperature aboutRT, then 2,6-dibromopyridine 77 is added and reacted at a temperatureabove RT, preferably at a temperature above about 50° C., morepreferably at about 90° C. to form the pyrrolidinyl ether 79.

[0360] 2-(Piperidinyl)pyridines 83 are prepared as described in Scheme22. Strong base, such as n-BuLi, in a solvent such as dry THF, is addedto dibromopyridine 77 at a temperature less than RT, preferably belowabout −50° C., more preferably at about −70° C. 4-Methylpiperidone isadded to form the 4-hydroxy-piperidine 80 at a temperature less than RT,preferably below about −50° C., more preferably at about −70° C. The4-hydroxy piperidine 80 is hydrated, such as with strong acid,preferably H₂SO₄, at a temperature above RT, preferably above 75° C.,more preferably at about 100° C., to form the tetrahydro-bipyridine 81.The 2-bromo-pyridine 81 is aminated, such as with NH₄OH, in the presenceof Cu powder at a temperature above RT, preferably above about 75° C.,more preferably at about 100° C., to form the amino-pyridine 82.Preferably the reaction is run in a sealed tube. The1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6-ylamine is hydrogenated, suchas with H₂ in the presence of Pd(OH)₂/C, at a temperature of about RT,to form the piperidinyl pyridine 83.

[0361] Thiazolyl indazoles 87 can be prepared from anilines as outlinedin Scheme 23. Similar to the method of J. Sun, et al, J.Org.Chem., 1997,p. 5627, protected 1H-indazole-5-carbonitrile 85 is prepared from4-amino-3-methylbenzonitrile 84 in the presence of acetic anhydride, andKOAc in an appropriate solvent such as CHCl₃. The protected1H-indazole-5-carbothioic acid amide 85 is prepared from thecarbonitrile 84 by treatment with H₂S gas in the presence of base, suchas Et₃N and solvent, such as THF, at a temperature below RT, preferablyat about 0° C. The amide 86 is added to a diketo compound, such asethylbromopyruvate at a temperature above RT, preferably above about 50°C., more preferably at reflux, in an appropriate solvent such as EtOH,to form the thiazolyl indazole ester. The ester is hydrolyzed with base,such as with LiOH at a temperature of about RT to yield the free acid87. Additionally, the indazole may be acylated, such as with Ac₂O.

[0362] Disubstituted aminopyridines 91 can be prepared from thecorresponding acids 88, where R^(c) is heterocyclyl, as described inScheme 24. Carboxylic acid or the corresponding ester is reduced, suchas with BH₃-THF solution in a solvent, such as in dry THF, at atemperature of about RT, to form the alcohols 89. Oxalyl chloride andDMSO in a solvent such as dry CH₂Cl₂, is treated with the alcohol 89 inthe presence of base, such as TEA at a temperature of about RT, to formthe aldehyde 90. The aldehyde 90 is coupled with an heteroaryl group,such as diaminopyridine in a solvent such as dry CH₂Cl₂, via reductiveamination for example in the presence of NaBH(OAc)₃, piperidine andHOAc, at a temperature above RT, preferably at about 40° C., to form thesubstituted amino pyridine 91.

[0363] N-Oxides can be obtained in a known matter by reacting a compoundof Formula I-VI with hydrogen peroxide or a peracid, e.g.3-chloroperoxy-benzoic acid, in an inert solvent, e.g. CH₂Cl₂, at atemperature between about −10 to about 35° C., such as about 0° C. toabout RT.

[0364] In the preparation of starting materials, existing functionalgroups, for example carboxy, hydroxy, amino, or mercapto, which do notparticipate in the reaction should, if necessary, be protected. Suchprotecting groups are those or similar to those usually used in thesynthesis of peptide compounds, cephalosporins, penicillins, nucleicacid derivatives or sugars. Preferred protecting groups, theirintroduction and their removal are described above or in the examples.

[0365] The protecting groups may already be present in precursors andshould protect the functional groups concerned against unwantedsecondary reactions, such as acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readyremoval, i.e. without undesired secondary reactions, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products. One skilled in the art knows,or can easily establish, which protecting groups are suitable with thereactions mentioned above and hereinafter.

[0366] The protection of such functional groups by such protectinggroups, the protecting groups themselves, and their removal reactionsare described for example in standard reference works, such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973, in T. W. Greene, “Protective Groups in OrganicSynthesis”, Wiley, New York 1981, in “The Peptides”; Volume 3 (editors:E. Gross and J. Meienhofer), Academic Press, London and New York 1981,in “Methoden der organischen Chemie” (Methods of organic chemistry),Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart1974, in H. -D. Jakubke and H. Jescheit, “Aminosäuren, Peptide,Proteine” (Amino acids, peptides, proteins), Verlag Chemie, Weinheim,Deerfield Beach, and Basel 1982, and in Jochen Lehmann, “Chemie derKohlenhydrate: Monosaccharide und Derivate” (Chemistry of carbohydrates:monosaccharides and derivatives), Georg Thieme Verlag, Stuttgart 1974.

[0367] In the additional process steps, carried out as desired,functional groups of the starting compounds which should not take partin the reaction may be present in unprotected form or may be protectedfor example by one or more of the protecting groups mentioned aboveunder “protecting groups”. The protecting groups are then wholly orpartly removed according to one of the methods described there.

[0368] In certain cases, typically in hydrogenation processes, it ispossible to achieve stereoselective reactions, allowing for exampleeasier recovery of individual isomers.

[0369] The solvents from which those can be selected which are suitablefor the reaction in question include, for example, water, esters,typically lower alkyl-lower alkanoates, e.g EtOAc, ethers, typicallyaliphatic ethers, e.g. Et₂O, or cyclic ethers, e.g. THF, liquid aromatichydrocarbons, typically benzene or toluene, alcohols, typically MeOH,EtOH or 1-propanol or iPrOH, nitriles, typically CH₃CN, halogenatedhydrocarbons, typically CH₂Cl₂, acid amides, typically DMF, bases,typically heterocyclic nitrogen bases, e.g. pyridine, carboxylic acids,typically lower alkanecarboxylic acids, e.g. AcOH, carboxylic acidanhydrides, typically lower alkane acid anhydrides, e.g. Ac₂O, cyclic,linear, or branched hydrocarbons, typically cyclohexane, hexane, orisopentane, or mixtures of these solvents, e.g. aqueous solutions,unless otherwise stated in the description of the process.

[0370] The invention relates also to those forms of the process in whichone starts from a compound obtainable at any stage as a transient andcarries out the missing steps, or breaks off the process at any stage,or forms a starting material under the reaction conditions, or uses saidstarting material in the form of a reactive derivative or salt, orproduces a compound obtainable by means of the process according to theinvention and processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described above as preferred.

[0371] The compounds of Formula I-VI, including their salts, are alsoobtainable in the form of hydrates, or their crystals can include forexample the solvent used for crystallization (present as solvates).

[0372] New starting materials and/or intermediates, as well as processesfor the preparation thereof, are likewise the subject of this invention.In the preferred embodiment, such starting materials are used andreaction conditions so selected as to enable the preferred compounds tobe obtained.

[0373] Starting materials of the invention, are known, are commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art.

[0374] All remaining starting materials are known, capable of beingprepared according to known processes, or commercially obtainable; inparticular, they can be prepared using processes as described above oras in the examples.

[0375] The compounds of this invention may contain one or moreasymmetric centers and thus occur as racemates and racemic mixtures,scalemic mixtures, single enantiomers, individual diastereomers anddiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included in the present invention.

[0376] The compounds of this invention may also be represented inmultiple tautomeric forms, for example, as illustrated below:

[0377] The invention expressly includes all tautomeric forms of thecompounds described herein.

[0378] The compounds may also occur in cis- or trans- or E- or Z-doublebond isomeric forms. All such isomeric forms of such compounds areexpressly included in the present invention. All crystal forms of thecompounds described herein are expressly included in the presentinvention.

[0379] Substituents on ring moieties (e.g., phenyl, thiazolyl, etc.) maybe attached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

[0380] The compounds of this invention may contain heterocyclic ringsystems attached to another ring system. Such heterocyclic ring systemsmay be attached through a carbon atom or a heteroatom in the ringsystem.

[0381] A compound of any of the formulas delineated herein may besynthesized according to any of the processes delineated herein. In theprocesses delineated herein, the steps may be performed in an alternateorder and may be preceded, or followed, by additionalprotection/deprotection steps as necessary. The processes may furthercomprise use of appropriate reaction conditions, including inertsolvents, additional reagents, such as bases (e.g., LDA, DIEA, pyridine,K₂CO₃, and the like), catalysts, and salt forms of the above. Theintermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase,simulated moving bed (“SMB”)), extraction, distillation, trituration,reverse phase HPLC and the like. Reactions conditions such astemperature, duration, pressure, and atmosphere (inert gas, ambient) areknown in the art and may be adjusted as appropriate for the reaction.Additionally, the compounds can be produced metabolically.

[0382] As can be appreciated by one skilled in the art, the abovesynthetic schemes are not intended to comprise a comprehensive list ofall means by which the compounds described and claimed in thisapplication may be synthesized. Further methods will be evident to thoseof ordinary skill in the art. Additionally, the various synthetic stepsdescribed above may be performed in an alternate sequence or order togive the desired compounds. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the inhibitor compounds described herein are known in theart and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. Greeneand P. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., JohnWiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995); P. Lopez et al., Synthesis 2, 186 (1998); A.Mikhalev, et al., Khim. Geterotsikl Soedin, 5, 697 (1997); M. Fernandez,et al., Synthesis, 11, 1362 (1995); P. Desos, et al., J. Med. Chem, 39,197 (1996); G. Timari, et al., Synlett, 9, 1067 (1997); Y. Tagawa, etal., J. Heterocycl. Chem., 34, 1677 (1997); A. Fuerstner, et al., Chem.Sci. 50, 326 (1995); A. Katritzky and A. Pozharski, Handbook ofHeterocyclic Chemistry, 2^(nd) Ed. (2001); and WO01/132658.

[0383] The compounds of this invention may be modified by appendingappropriate functionalities to enhance selective biological properties.Such modifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

[0384] The following examples contain detailed descriptions of themethods of preparation of compounds of Formulas I-VI. These detaileddescriptions fall within the scope, and serve to exemplify, the abovedescribed General Synthetic Procedures which form part of the invention.These detailed descriptions are presented for illustrative purposes onlyand are not intended as a restriction on the scope of the invention. Allparts are by weight and temperatures are in Degrees centigrade unlessotherwise indicated. All compounds showed NMR spectra consistent withtheir assigned structures.

[0385] The following abbreviations are used: AcOH, HOAc - acetic acidAc₂O - acetic anhydride AcCN, CH₃CN - acetonitrile ATP - adenosinetriphosphate NH₃ - ammonia NH₄OH - ammonium hydroxide NH₄Cl - ammoniumchloride AIBN - 2,2′-azobis-isobutyrlnitrile HATU -O-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate BOP-Cl - bis(2-oxo-3-oxazolidinyl)phosphinicchloride PdCl₂(dppf) - 1,1-bis(diphenylphosphino)ferrocene palladiumchloride BH₃-THF - borane-tetrahydrofuran BSA - bovine serum albuminBOC - tert-butyloxycarbonyl BuLi - n-butyllithium Boc₂O - di-tert-butyldicarbonate, BOC anhydride CCl₄ - carbon tetrachloride CHCl₃ -chloroform Cu - copper CuBr - copper (I) bromide CuI₂ - copper (II)iodide CuSO₄ ₋ copper (II) sulfate CH₂Cl₂ - dichloromethane, methylenechloride Pd(PhCN)₂Cl₂ - dichlorobis(benzonitrile)palladium DEA, Et₂NH -diethylamine Et₂O - diethyl ether DIEA - diisopropylethylamine DIBAL-H -diisobutylaluminum hydride DME - 1,2-dimetoxyethane EDC, EDCI -1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride DMAP -4-(dimethylamino)pyridine DMF - dimethylformamide DMSO -dimethylsulfoxide DPPA, (PhO)₂PON₃ - diphenylphosphoryl azide DTT -dithiothreitol EtOH - ethanol EtOAc - ethyl acetate EGTA - ethyleneglycol-bis(β-aminoethyl ether)- N,N,N′, N′-tetraacetic acid EDTA -ethylenediaminetetraacetic acid g - gram h - hour HCl - hydrochloricacid HBr - hydrobromic acid H₂S - hydrogen sulfide HOBt -hydroxybenzotriazole IpOH - isopropanol LAH, LiAlH₄ - lithium aluminumhydride LiOH - lithium hydroxide MgCl₂ - magnesium chloride MgSO₄ -magnesium sulfate MnCl₂ - manganese chloride MeOH - methanol MeMgI -methyl magnesium iodide mg - milligram ml, mL - milliliter min - minutesNBS - N-bromosuccinimide N₂ - nitrogen Pd(OH)₂/C - palladium hydroxideon carbon H₃PO₄ - phosphoric acid P₂S₅ - phosphorous pentasulfide PtO₂ -platinum oxide KOAc - potassium acetate KOH - potassium hydroxide pyr -pyridine RT - room temperature Na₂SO₄ - sodium sulfate Na₂CO₃ - sodiumcarbonate NaCNBH₃ - sodium cyanoborohydride NaBH₄ - sodium borohydrideNaOH - sodium hydroxide NaOEt - sodium ethoxide NaOMe - sodium methoxideNaBr - sodium bromide NaCl - sodium chloride NaCN - sodium cyanideNaNO₂ - sodium nitrite NaN₃ - sodium azide SOV - sodium orthovanadateNaBH(OAc)₃ - sodium trisacetoxy borohydride NaH - sodium hydrideNaHCO₃ - sodium bicarbonate H₂SO₄ - sulfuric acid THF - tetrahydrofuranTsOH - Toluenesulfonic acid t-Bu₃P - tri-tert-butylphosphine TEA, Et₃N -triethylamine TFA - trifluoroacetic acid Tris-HCl -Tris(hydroxymethyl)aminomethane hydrochloride salt H₂O - water

[0386] Preparation A: 2-Amino-6-morpholinopyridine:

[0387] A mixture of 2-chloro-6-aminopyridine (200 mg, 1.49 mmol),morpholine (326 mg, 3.75 mmol) and phenol (2 g) was heated at 150° C.for 20 h. After cooling to RT, 3N NaOH (10 mL) was added and the mixturewas extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude was purified by chromatography on silica gel (1:10MeOH/CH₂Cl₂) to afford the morpholino derivative as an amber oil. MSm/z: 180 (M+1).

[0388] Preparation B: 2-Bromo-6-N,N-diethylamidopyridine:

[0389] Ethyl chloroformate (1.76 g, 16.3 mmol) was added dropwise to amixture of 6-bromopicolinic acid (3 g, 14.8 mmol) and Et₃N (1.8 g, 17.8mmol) in THF (150 mL) at 0° C. After the mixture was stirred for 1 h,DEA (1.3 g, 17.8 mmol) was added slowly to the mixture at 0° C. Theresulting mixture was stirred at RT for 5 h. H₂O (200 mL) was added andthe mixture was extracted with EtOAc (3×120 mL). The combined organiclayers were washed with 1N NaOH and brine, dried over Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to afford2-bromo-6-N,N-diethylamidopyridine as an amber oil. MS m/z: 259 (M+1).

[0390] Preparation C: 2-Amino-6-N,N-diethylamidopyridine:

[0391] A mixture of 2-bromo-6-N,N-diethylamidopyridine (3.5 g), 50 mL of37% NH₄OH and 0.8 g of Cu powder in 40 mL of IpOH was heated at 100° C.in sealed tube for 20 h. After cooling to RT, brine was added and themixture was extracted with EtOAc (3×120 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo to afford the amino derivative as a light amber solid. MS m/z: 194(M+1).

[0392] Preparation D: 2-Amino-6-N,N-diethylaminamethylpyridine:

[0393] To a solution of 2-amino-6-N,N-diethylamidopyridine (2.2 g, 11.4mmol) in 200 mL of THF was added slowly 34.2 mL of LiAlH₄ (1.3 g, 34.2mmol) solution in Et₂O at 0° C. The resulting mixture was heated atreflux for 6 h. After cooling to 0° C., 2 mL of H₂O, 1.3 mL of 15% NaOHand 7.5 mL of H₂O was added to the mixture sequentially. After stirringfor 2 h at RT, the mixture was filtered through Celite®. The filtratewas concentrated and purified by chromatography on silica gel (1:10MeOH(NH₃)/CH₂Cl₂) to afford the aminomethyl compound as an amber oil. MSm/z: 180 (M+1).

[0394] Preparation E: 2-Amino-6-(N-methylpiperazinyl)pyridine:

[0395] A mixture of 2-bromo-6-aminopyridine (3 g, 17.34 mmol),1-methylpiperizine (2.3 g, 22.54 mmol) and Cu powder (0.5 g, 7.87 mmol)in 5 mL of 2,4-diethylphenol was heated at 150° C. for 20 h. Aftercooling to RT, 3N HCl (30 mL) was added and the mixture was extractedwith Et₂O (2×100 mL). The aqueous layer was basified with concentratedNH₄OH to pH>10 and then extracted with EtOAc (3×100 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude was purified by chromatography onsilica gel (1:10 MeOH(NH₃)/CH₂Cl₂) to afford the piperazinyl compound asa light amber solid. MS m/z: 193 (M+1).

[0396] Preparation F: 2-Amino-6-(4-morpholino)propylamino-pyridine:

[0397] A mixture of 2-bromo-6-aminopyridine (0.5 g, 2.92 mmol),4-(3-aminopropyl)morpholine (1.5 g 10.42 mmol) and Cu powder (0.6 g,9.52 mmol) in 15 mL of IpOH and 5 mL of H₂O was heated at 100° C. in asealed tube for 24 h. After cooling to RT, water was added and themixture was extracted with EtOAc (3×50 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The crude was purified by chromatography on silica gel (1:10MeOH(NH₃)/CH₂Cl₂) to afford the morpholino compound as an amber oil. MSm/z: 237 (M+1).

[0398] Pr paration G: 2-Amino-6-(2-N,N-dimethylamino)ethylaminopyridine:

[0399] A mixture of 2-bromo-6-aminopyridine (0.3 g, 1.17 mmol),N,N-dimethylethylenediamine (1 g, 11.36 mmol) and Cu powder (0.74 g,11.7 mmol) in 30 mL of IpOH was heated at 100° C. in sealed tube for 20h. After cooling to RT, H₂O was added and the mixture was extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated in vacuo. The crude waspurified by chromatography on silica gel (1:10 MeOH (NH₃)/CH₂Cl₂) toafford the compound as an oil. MS m/z: 181 (M+1).

[0400] Preparation H: Amino-2-pyridylmethane-1-thione:

[0401] 2-Cyanopyridine (2.6 g, 0.025 mol) was added to a solution of TEA(5.5 mL) and dry pyridine (50 mL) at RT. H₂S was bubbled through thesolution for 1 h. Afterwards, H₂O (150 mL) was added and the mixture wasextracted with EtOAc (3×50 mL) . The EtOAc extracts were dried overNa₂SO₄, filtered, and the solvent was removed under vacuum. Theresulting residue was purified by column chromatography eluting withhexanes:EtOAc (4:1) to give amino-2pyridylmethane-1-thione as a lightyellow solid. GC/MS m/z: 139 (M+H); GC Retention time: 7.93 min.

[0402] Preparation I: 2-(2-Pyridinyl)thiazole-4-carboxylic acid:

[0403] Amino-2-pyridylmethane-1-thione (1.88 g, 0.0136 mol), ethylbromopyruvate (1.80 mL, 0.0143 mol) and EtOH (30 mL) were combined andheated to reflux. GC/MS of reaction mixture after 3 h showed totalconsumption of the starting materials. After cooling to RT, the solventwas removed under vacuum resulting in a dark brown oil (GC/MS m/z: 235(M+H); GC Retention time: 10.69 min). The material was taken up in MeOH(20 mL), 1.0M LiOH—H₂O (20 mL) was added and the mixture was heated to100° C. for 14 h. After cooling to RT, the excess MeOH was evaporatedand the resulting brown solid filtered. The material was washed with aminimum of H₂O and dried in vacuo to give the thiazole as a brown solid.

[0404] Preparation J: 2-(4-Pyridinyl)-4-thiazolylcarbonylazide:

[0405] To a suspension of 2-(4-pyridinyl)-4-thiazolyl carboxylic acid(Maybridge Chem., 6.0 g, 29.1 mmol) in 150 mL MeOH at RT was added NaOH(1.28 g, 32.0 mmol) and the mixture was stirred at RT for 45 min. Thereaction mixture was concentrated in vacuo then dried under high vacuumfor 60 h (overnight drying is a minimum). The crude salt was suspendedin 150 mL of CH₂Cl₂ and cooled in an ice bath. Oxalyl chloride (2.8 mL)was added slowly to the suspension followed by a catalytic amount of DMF(0.2 mL). The mixture was stirred for 2 h and warmed to RT. The reactionwas cooled in an ice bath and a solution of NaN₃ (2.27 g) in water (90mL) was added and stirring was continued for 3 h. The reaction mixturewas diluted with water (90 mL) and extracted with CH₂Cl₂ (3×75 mL). Thecombined organic layers were filtered through Celitee® (˜12 g) washedwith 90 mL brine, dried with MgSO₄ and concentrated in vacuo. Drying thecrude compound on the vacuum line afforded the azido derivative as alight brown solid. MS m/z: 204.5 (M−N₂+H).

[0406] Preparation K: 2-(3-Pyridinyl)-4-thiazolylcarbonylazide:

[0407] In a manner similar to that described for the preparation of2-(4-pyridinyl)-4-thiazolylcarbonylazide, 6.0 g of2-(3-pyridinyl)-4-thiazolylcarboxylic acid was treated successively withNaOH, oxalyl chloride and a solution of NaN₃ in water to give the3-pyridinylazide as a pale brown solid. MS m/z: 204.5 (M—N₂+H).

[0408] Preparation L: 2-(2-Pyridinyl)-4-thiazolylcarbonylazide:

[0409] In a manner similar to that described for the preparation of2-(4-pyridinyl)-4-thiazolyl-carbonylazide,2-(2-pyridinyl)-4-thiazolylcarboxylic acid (1.0 g)was treatedsuccessively with NaOH, oxalyl chloride and a solution of NaN₃ in waterto give the 2-pyridinyl azide as a pale brown solid: m.p. 112-114° C. MSm/z: 232 (M+H)

[0410] Preparation M: 2-Phenyl-4-thiazolylcarbonylazide:

[0411] In a manner similar to that described for the preparation of2-(4-pyridinyl)-4-thiazolylcarbonyl-azide, 1.0 g of2-phenyl-4-thiazolylcarboxylic acid was treated successively with NaOH,oxalyl chloride and a solution of NaN₃ in water to give the phenylazideas an off white solid. MS m/z: 203.5 (M−N₂+H).

[0412] Preparation N: 4-(6-Bromo-pyridin-2-ylmethyl)-morpholine

[0413] To a stirred solution of 6-bromo-2-pyridine-carboxaldehyde (200mg, 1.08 mmol) in dichloroethane (10 mL) was added morpholine (0.14 mL,1.62 mmol) followed by NaBH(OAc)₃ (458 mg, 2.16 mmol) and AcOH (0.25 mL,4.32 mmol). The resulting mixture was stirred at RT for 12 h. Thereaction was quenched with 2M Na₂CO₃ solution and stirred 1 h. Themixture was poured into Et₂O and washed with 2 M Na₂CO₃ solution. Theorganic layer was collected, dried over Na₂SO₄ and concentrated in vacuoto give 2-bromo-6-morpholinyl-methylpyridine as a white solid. MS m/z:256.9 (M+H).

[0414] The following compounds were prepared in a manner similar to thatdescribed above:

[0415] 1] 1-(6-Bromopyridin-2-ylmethyl)-piperidine-4-carboxylic acidethyl ester, as a pale yellow solid, was prepared in a manner similar tothat described in General Preparation N[6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.16 mmol) was added to ethylisonipecotate (0.5 mL, 3.24 mmol) in dry CH₂Cl₂ (10 mL)]. MS m/z: 327.0(M+H). Calc'd for C₁₄H₁₉BrN₂O₂: 326.90.

[0416] 2] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.16 mmol) wasadded L-leucinol (0.42 mL, 3.24 mmol) in dry CH₂Cl₂ (10 mL) to give2-[(6-bromo-pyridin-2-ylmethyl)-amino]-4-methyl-pentan-1-ol as brownsolid. MS m/z: 287.6 (M+H). Calc'd for C₁₂H₁₉BrN₂O: 287.2.

[0417] 3] To 6-bromo-2-pyridinecarboxaldehyde (500 mg, 2.69 mmol) wasadded 1,4-dioxa-8-azaspiro-[4,5]-decane (0.5 mL, 4.03 mmol) in dryCH₂Cl₂ (10 mL) to give2-bromo-6-(4-ethoxyacetal)-piperidinylmethylpyridine as white solid. MSm/z: 313 (M+H). Calc'd for C₁₃H₁₇BrN₂O2: 313.2.

[0418] 4] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) wasadded 3,5-dimethylpiperidine (0.4 mL, 3.22 mmol) in dry CH₂Cl₂ (10 mL)to give 2-bromo-6-(3,5-dimethyl)piperidinylmethyl pyridine as whitesolid. MS m/z: 283.2 (M+H). Calc'd for C₁₃H₁₉BrN₂: 283.2

[0419] 5] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) wasadded 4-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH₂Cl₂ (10 mL) togive 2-bromo-6-[(4-A-methyl)piperidinylmethyl]pyridine as a white solid.MS m/z: 269.4 (M+H). Calc'd for C₁₂H₁₇BrN₂: 269.18.

[0420] 6] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) wasadded 2-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH₂Cl₂ (10 mL) togive 2-bromo-6-[(2-methylpiperidinyl)methyl]pyridine as a pale yellowsolid. MS m/z: 269.1(M+H). Calc'd for C₁₂H₁₇BrN₂: 269.18.

[0421] 7] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) wasadded 4-(1-pyrrolidinyl)-piperidine (500 mg, 3.22 mmol) in dry CH₂Cl₂(15 mL) to give 2-bromo-6-[4-(1-pyrrolidinyl)piperidinylmethyl]pyridineas a pale yellow solid. MS m/z: 326.1(M+2H). Calc'd for C₁₅H₂₂BrN₃:324.26.

[0422] 8] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) wasadded 3-hydroxypiperidine (326 mg, 3.22 mmol) in dry CH₂Cl₂ (15 mL) togive 2-bromo-6-(3-hydroxypiperidinyl)methyl pyridine as pale yellowsolid. MS m/z: 271.2 (M+H). Calc'd for C₁₁H₁₅BrN₂O: 271.15.

[0423] 9] To 6-bromo-2-pyridinecarboxaldehyde (300 mg, 1.62 mmol) wasadded hexamethyleneimine (0.27 mL, 2.43 mmol) in dry CH₂Cl₂ (10 mL) togive 2-bromo-6-(azaperhydroepinylmethyl)pyridine as a white solid. MSm/z: 270.3(M+H). Calc'd for C₁₂H₁₇BrN₂: 269.18.

[0424] 10] To 4-hydroxypiperidine (143 mg, 1.41 mmol) was added asolution of 6-bromo-2-pyridine-carboxaldehyde (200 mg, 1.08 mmol) togive 2-bromo-6-[(4-hydroxypiperidyl)methyl]-pyridine as a white solid.MS m/z: 271.0 (M+H). Calc'd for C₁₁H₁₅BrN₂O—271.15.

[0425] 11] 3-Hydroxypropylamine (0.15 mL, 2.02 mmol) was added to asolution of 6-bromo-2-pyridine-carboxaldehyde (250 mg, 1.35 mmol) togive 2-bromo-6-[(3-hydroxypropyl)amino]-methylpyridine as a white solid.MS m/z: 245.1 (M+H). Calc'd for C₁₁H₁₃BrN₂O—245.19.

[0426] 12] Ethyl(piperidyl-3-carboxylate (0.92 mL, 5.92 mmol) was addedto a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) togive ethyl 1-[(6-bromopyridin-2-yl)methyl]-piperidine-3-carboxylate as acolorless oil. MS m/z: 327.1 (M+H). Calc'd for C₁₄H₁₉BrN₂O₂—327.22.

[0427] 13] Ethyl (2-piperidyl)carboxylate (0.92 mL, 5.92 mmol) was addedto a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0 g, 5.38 mmol) togive ethyl 1-[(6-bromopyridin-2-yl)methyl]-piperidine-2-carboxylate as acolorless oil). MS m/z: 327.1 (M+H). Calc'd for C₁₄H₁₉BrN₂O₂—327.22.

[0428] 14] N,N-Diethylcarbamoyl-piperidine-3-carboxamide (0.92 mL, 5.92mmol) was added to a solution of 6-bromo-2-pyridinecarboxaldehyde (1.0g, 5.38 mmol) to give N,N-diethyl1-(6-bromopyridin-2-ylmethyl)piperidine-3-carboxamide as a colorlessoil. MS m/z: 354.1 (M+H). Calc'd for C₁₆H₂₄BrN₃O—354.29.

[0429] 15] 2-Pyrrolidine carboxylic acid (0.68 g, 5.92 mmol) was addedto a solution of 6-bromo-2-pyridine-carboxaldehyde (1.0 g, 5.38 mmol) togive 1-(6-bromopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acid as awhite solid. MS m/z: 285.1 (M+H). Calc'd for C₁₁H₁₃BrN₂O₂—285.14.

[0430] 16] 3-Methylpiperidine (0.33 mL, 2.8 mmol) was added to asolution of 6-bromo-2-pyridine-carboxaldehyde (350 mg, 1.88 mmol) togive 2-bromo-6-[(3-methylpiperidyl)methyl]pyridine as a white solid. MSm/z: 269.1 (M+H). Calc'd for C₁₂H₁₇BrN₂—269.18.

[0431] Preparation O: 6-Morpholin-4-ylmethyl-pyridin-2-ylamine

[0432] NH₄OH (2 mL) and Cu powder (10 mg, 0.15 mmol) were added to asolution of 2-bromo-6-morpholinylpyridine (231 mg, 0.90 mmol) in IpOH (5mL) and the resulting mixture was heated at 100° C. for 36 h in a sealedtube. After cooling to RT, the mixture was partitioned between H₂O andEtOAc. The organic layer was collected, washed with brine, and driedover Na₂SO₄. Concentration in vacuo gave the tilted compound as a paleyellow solid. MS m/z: 194.1 (M+H).

[0433] The following amines were prepared from the corresponding bromocompounds (prepared by Preparation N) in a manner similar to thatdescribed in General Preparation O:

[0434] 1] 1-(6-amino-pyridin-2-ylmethyl)-piperidine-4-carboxylic acidethyl ester as brown liquid. MS m/z: 264.2 (M+H). Calc'd for C₁₄H₂₁N₃O₂:263.34.

[0435] 2]2-amino-6-[N′-tert-butoxycarbonyl-N′-2-(1-hydroxy-4-methyl)pentylaminolmethylpyridineas a brown liquid. MS m/z: 324.3 (M+H). Calc'd for C₁₇H₂₉N₃O₃: 323.2.

[0436] 3] 2-amino-6-(4-ethoxyacetalpiperidinyl)-methylpyridine as awhite solid. MS m/z: 250 (M+2H). Calc'd for C₁₃H₁₉N₃O₂: 249.1.

[0437] 4] 2-Amino-6-(3,5-dimethylpiperidinyl)methyl-pyridine as a yellowsolid. MS m/z: 220.3 (M+H). Calc'd for C₁₃H₂₁N₃: 219.

[0438] 5] 2-Amino-6-(4-methylpiperidinyl)methylpyridine as a yellowsolid. MS m/z: 206.3 (M+H). Calc'd for C₁₂H₁₉N₃: 205.28.

[0439] 6] 2-Amino-6- (2-methylpiperidinyl)methylpyridine as a yellowliquid. MS m/z: 206.3 (M+H). Calc'd for C₁₂H₁₉N₃: 205.28.

[0440] 7] 2-Amino-6-[[4-(1-pyrrolidinyl)piperidinyl]methyl]-pyridine asa brown liquid. MS m/z: 261.1 (M+2H). Calc'd for C₁₂H₁₉N₃: 260.

[0441] 8] 2-Amino-6-(3-hydroxypiperidinyl)methylpyrine as a yellowliquid. MS m/z: 410.9 (M+H). Calc'd for C₁₁H₁₇N₃O: 410.5.

[0442] 9] 2-Amino-6-(azaperhydroepinylmethyl)pyridine as a white solid.MS m/z: 206.1 (M+H). Calc'd for C₁₂H₁₉N₃: 205.32.

[0443] 10] 2-Amino-6-[(4-hydroxypiperidyl)methyl]pyridine as a paleyellow oil. MS m/z: 208.1 (M+H). Calc'd for C₁₁H₁₇N₃O—207.27.

[0444] 11]2-Amino-6-[(N-tert-butoxycarbonyl-N-(3-hydroxypropyl)amino]methylpyridineas a pale yellow oil. MS m/z: 282.3 (M+H). Calc'd for C₁₄H₂₃N₃O₃—281.35.

[0445] 12] Ethyl1-[(6-aminopyridin-2-yl)methyl]-piperidine-3-carboxylate as a paleyellow oil. MS m/z: 264.1 (M+H). Calc'd for C₁₄H₂₁N₃O₂—263.34.

[0446] 13] Ethyl1-[(6-aminopyridin-2-yl)methyl]-piperidine-2-carboxylate as a paleyellow oil. MS m/z: 264.1 (M+H). Calc'd for C₁₄H₂₁N₃O₂—263.34.

[0447] 14] N,N-Diethyl1-(6-aminopyridin-2-ylmethyl)-piperidine-3-carboxamide as a pale yellowoil. MS m/z: 291.5 (M+H). Calc'd for C₁₆H₂₆N₄O—290.40.

[0448] 15] 1-(6-Aminopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acidas a white solid. MS m/z: 220.3 (M−H). Calc'd for C₁₁H₁₅N₃O₂—221.26.

[0449] 16] 2-Amino-6-[(3-methylpiperidyl)methyl]pyridine as a paleyellow solid. MS m/z: 206.5 (M+H). Calc'd for C₁₂H₁₉N₃—205.30.

[0450] 17] 1-(6-Aminopyridin-2-ylmethyl)-piperidine-3-carboxylic acid asa pale yellow oil. MS m/z: 235.0 (M+H). Calc'd for C₁₂H₁₇N₃O₂—235.28.

[0451] Preparation P: 4-(6-Aminopyridin-2-yloxy)-benzonitrile

[0452] To a stirred solution of 4-cyanophenol (1.7 g, 14.3 mmol) in 45mL dry DMF was added NaH (0.71 g, 17.7 mmol). After stirring at RT for15 min, 2,6-dibromopyridine (3.2 g, 13.4 mmol) was added and the mixturewas heated at 95° C. for 24 h. After cooling to RT, 100 mL of H₂O wasadded and the mixture was extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with 40 mL brine, dried over MgSO₄ andconcentrated in vacuo. The crude intermediate was dissolved in 20 mLIpOH, transferred to a Teflon lined pressure vessel and 20 mL of conc.NH₄OH was added. Powdered Cu (1 g) was added and the vessel was sealedand heated at 140° C. for 24 h. After cooling to RT, the Cu was removedby filtration and the filtrate was diluted with 75 mL of H₂O andextracted with EtOAc (2×75 mL). The organic layers were washed withbrine, dried over MgSO₄ and concentrated in vacuo. The compound waspurified by chromatography on silica gel using 10:1 CHCl₃/(˜2M NH₃/MeOH)as eluent to afford the title compound as a dark oil. MS m/z: 212.2(M+H).

[0453] The following compounds were prepared from 2,6-dibromopyridine ina manner similar to that described in General Preparation P:

[0454] 1] 6-Phenoxy-pyridin-2-ylamine: MS m/z: 187.2 (M+H). Calc'd forC₁₁H₁₀N2O: 186.08.

[0455] 2] 6-(4-Methylphenyloxy)pyridin-2-ylamine: MS m/z: 201.3 (M+H).Calc'd for C₁₂H₁₂N₂O: 200.09.

[0456] 3] 6-(2,4-Dimethylphenyloxy)pyridin-2-ylamine: MS m/z: 215.3(M+H). Calc'd for C₁₃H₁₄N₂O: 214.11.

[0457] 4] 6-[4-(1-Imidazolyl)phenyloxylpyridin-2-ylamine: MS m/z: 253.3(M+H). Calc'd for C₁₄H₁₂N₄O: 252.10.

[0458] 5] 6-[4-[1,3]Dioxolan-2-yl-phenoxy)pyridin-2-ylamine: MS m/z:259.3 (M+H). Calc'd for C₁₄H₁₄N₂O₃: 258.10.

[0459] 6] 6-(4-Fluorophenyloxy)pyridin-2-ylamine: MS m/z: 205.2 (M+H).Calc'd for C₁₁H₉FN₂O: 204.07.

[0460] 7] 6-(4-Difluorophenyloxy)pyridin-2-ylamine: MS m/z: 223.2 (M+H).Calc'd for C₁₁H₈F₂N₂O: 222.06.

[0461] 8] tert-Butyl{2-[4-(6-aminopyridin-2-yloxy)phenyl]ethyl}carbamate: MS m/z: 330.4(M+H). Calc'd for C₁₈H₂₃N₃O₃: 329.17.

[0462] 9] 6-(2-Dimethylaminoethoxy)pyridin-2-ylamine: MS m/z: 182.2(M+H). Calc'd for C₉H₁₅N₃O: 181.12.

[0463] 10] 6-[(1-Methylpyrrolidin-2-yl)methoxy]pyridin-2-ylamine: MSm/z: 208.3 (M+H). Calc'd for C₁₁H₁₇N₃O: 207.14.

[0464] 11] 6-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)pyridin-2-ylamine: MS m/z:220.3 (M+H). Calc'd for C₁₂H₁₇N₃O: 219.14.

[0465] 12] tert-Butyl3-[(6-aminopyridin-2-yl)oxymethyl]-azetidine-1-carboxylate: MS m/z: 280(M+H). Calc'd for C₁₄H₂₁N₃O₃: 279.16.

[0466] 13] tert-Butyl4-[2-(6-Aminopyridin-2-yloxy)ethyl]-piperidine-1-carboxylate: MS m/z:322 (M+H). Calc'd for C₁₇H₂₇N₃O₃: 321.21.

[0467] Preparation Q:2-Bromo-6-[N′-tert-butoxycarbonyl-N′-2-(1-hydroxy-4-methyl)pentylamino]methylpyridine

[0468] To 2-bromo-6-[2-N-(1-hydroxy-4-methyl)-pentylamino]methylpyridine(550 mg, 1.91 mmol) in dry CH₂Cl₂ (10 mL) was added (Boc)₂O (460 mg,2.106 mmol). The resulting mixture was stirred under N₂ at RT for 15 h.The solvent was removed and the residue was extracted with CHCl₃. Theorganic layer was wash with H₂O, brine, and dried over MgSO₄ and removedto give a yellow liquid. MS m/z:387.6(M+H). Calc'd for C₁₇H₂₇BrN₂O₃:387.32.

[0469] The following BOC protected compounds were prepared from thecorresponding amines (prepared by Preparation N) in a manner similar tothat described in General Preparation Q:

[0470] 1]2-Bromo-6-[(N-tert-butoxycarbonyl-N-(3-hydroxypropyl)amino]methylpyridinewas prepared from 2-bromo-6-[(3-hydroxypropyl)-amino]-methylpyridine(300 mg, 1.22 mmol) [purified by chromatography on silica gel(hexane/acetone, 80/20]) as a colorless oil. MS m/z: 345.1 (M+H). Calc'dfor C₁₄H₂₁BrN₂O₃—345.23.

[0471] Preparation R:2,2-Dimethyl-N-[6-(2-methylimidazol-1-ylmethyl)pyridin-2-yl]propionamide

[0472] A solution of 2-methylimidazole (68 mg, 0.83 mmol) in dry THF (8mL) was treated under N₂ with NaH (33 mg, 0.83 mmol, 60% in mineral oil)at 0° C. After the addition, the mixture was warmed to RT and stirredfor 0.5 h. It was then treated dropwise with a solution ofN-pivaloyl-2-amino-6-bromomethylpyridine (150 mg, 0.55 mmol; M. V.Papadopoulou, et al., J. Heterocyclic Chem., 1995, 32, 675-681) in dryTHF (10 mL) over period of 15 min. After the addition, it was stirredfor 1 h. The resulting mixture was quenched with saturated NH₄Cl (3 mL). Solvent was removed and the residue was extracted with CHCl₃. Theorganic layer was washed with H₂O, brine, dried over MgSO₄, andconcentrated in vacuo to yield the title compound as light brownishsolid. MS m/z: 272.2 (M+H). Calc'd. for C₁₆H₂₁N₃O—271.37.

[0473] The following amines were prepared from the correspondingbromomethylpyridine in a manner similar to that described in PreparationR:

[0474] 1]2,2-Dimethyl-N-[6-(4-(N,N-dimethylaminomethyl)phenyloxymethyl)pyridin-2-yl]propionamide.MS m/z: 342 (M+H).

[0475] Preparation S:N-(6-Azidomethylpyridin-2-yl)-2,2-dimethylpropionamide

[0476] N-Pivaloyl-2-amino-6-bromomethylpyridine (1.1 g, 4.05 mmol; M. V.Papadopoulou, et al., J. Heterocyclic Chem., 1995, 32, 675-681) wasdissolved in dry THF (15 mL). NaN₃ (530 mg, 8.1 mmol) and dry DMF (5 mL)was added and the resulting mixture was heated to reflux under N₂ for 2h. After cooling to RT, solvent was removed and the residue waspartitioned between H₂O and CHCl₃. The organic layer was washed withH₂O, brine, dried over MgSO₄, and concentrated in vacuo to give thetitle compound as a pale yellow solid. MS m/z: 234.1 (M+H). Calc'd. forC₁₁H₁₅N₅O—233.28.

[0477] Preparation T: 6-Azidomethyl-pyridin-2-ylamine

[0478] 2-(N′-Pivaloyl)amino-6-azidomethylpyridine (680 mg, 2.91 mmol)was dissolved in MeOH (20 mL) and KOH was added (3.4 g, 60.6 mmol). Theresulting mixture was heated to reflux under N₂ for 2 h. After coolingto RT, pH was adjusted to 7 followed by removing the solvent. Theresidue was partitioned between H₂O and CHCl₃ and the aqueous layer wasextracted more with CHCl₃. The combined organic layers was washed withH₂O, brine, dried over MgSO₄, and concentrated in vacuo to yield thetitle compound as brown solid. MS m/z: 150.3 (M+H). Calc'd. for C₆H₇N₅:149.15.

[0479] The following amines were prepared from the corresponding bromocompounds (prepared by Preparations R-S, and AA) in a manner similar tothat described in Preparation T:

[0480] 1] 3-(2-Methylimidazol-1-ylmethyl)phenylamine. MS m/z: 189.3(M+H). Calc'd. for C₁₀H₁₂N₄—188.23.

[0481] 2] 2-Amino-6-[4-(dimethylamino)methyl]phenoxymethyl-pyridine. MSm/z: 258 (M+H).

[0482] 3]2-Amino-6-[1-(N-tert-butoxycarbonyl)amino]-ethoxymethyl-pyridine. MSm/z: 268 (M+H).

[0483] 4] 2-Amino-6-[4-(methylphenyl)oxymethyl]pyridine. MS m/z: 215(M+H).

[0484] 5]2-Amino-6-[1-(N-tert-butoxycarbonyl)amino]-ethoxymethyl-pyridine. MSm/z: 267 (M+H).

[0485] 6] 2-Amino-5-[1-morpholinylmethyl]pyridine. MS m/z: 194 (M+H).

[0486] 7] 5-Methoxymethyl-pyridin-2-ylamine.

[0487] Preparation U: Methyl1-(6-aminopyridin-2-ylmethyl)-pyrrolidine-2-carboxylate

[0488] Concentrated H₂SO₄ (1.0 mL) was added to a solution of1-(6-aminopyridin-2-ylmethyl)-pyrrolidine-2-carboxylic acid (620 mg,2.80 mmol) in MeOH (15 mL) and the resulting mixture was heated at 80°C. for 10 h. After cooling to RT, the mixture was quenched withsaturated 2 M Na₂CO₃ solution and concentrated in vacuo. CHCl₃ (15 mL)was added and the solution washed with 1.0 N NaOH solution (15 mL). Theorganics were collected and the aqueous layer was extracted withCHCl₃/IpOH (3/1, 3×10 mL). The combined organics were dried over MgSO₄and concentrated in vacuo. The crude compound was purified bychromatography on silica gel (CH₂Cl₂/MeOH, 95/5) to give a pale yellowoil. MS m/z: 236.1 (M+H). Calc'd for Cl₂H₁₇N₃O₂—235.28.

[0489] Preparation V: 3-Methyl-2-(phthalimidyl)pyridine

[0490] 2-Amino-3-picoline (1.00 mL, 8.62 mmol) was dissolved in DMF (30mL) at 23° C., and treated with solid carboethoxy-phthalimide (1.89 g,8.64 mmol), followed by TEA (1.44 mL, 10.3 mmol). The resulting solutionwas stirred at 23° C. for 15 h. After 15 h, the mixture was diluted withEtOAc (50 mL), and washed with saturated NaCl (1×50 mL), H₂O (1×50 mL),dried (MgSO₄), and concentrated in vacuo to a yellow solid. Purificationover silica gel (0 to 50% EtOAc/Hexanes) provided the title compound asa white solid.

[0491] Preparation W: 3-(Dibromomethyl)-2-(phthalimidyl)pyridine

[0492] 3-Methyl-2-(phthalimidyl)pyridine (360 mg, 1.51 mmol) wasdissolved in CCl₄ (5 mL), and treated with NBS (267 mg, 1.50 mmol),followed by AIBN (46.9 mg, 0.29 mmol). The resulting suspension waswarmed to reflux for 2 h, treated again with AIBN (55.4 mg, 0.34 mmol),and heated at reflux an additional 12 h. After 12 h, AIBN was againadded (96.7 mg, 0.59 mmol) and reflux was continued. After 2 h, moreAIBN was added (59.6 mg, 0.36 mmol), and reflux continued. After 2h,additional NBS was added (253 mg, 1.42 mmol) and the mixture was treatedwith additional AIBN (49.6 mg, 0.30 mmol), and heated at reflux anadditional 12 h. The mixture was cooled to RT, diluted with EtOAc (50mL), washed with saturated NaCl (1×50 mL) , then dried (MgSO₄) andconcentrated in vacuo. The resulting white solid was purified oversilica gel (0 to 40% EtOAc/Hexanes) to provide the title compound. MSm/z: 397 (M+H).

[0493] Preparation X: 2-(phthalimidyl)-3-(1-piperidinylmethyl)-pyridine

[0494] 3-(Dibromomethyl)-2-(phthalimidyl)pyridine (185 mg, 0.47 mmol)was dissolved in CH₂Cl₂ (2 mL) and treated with piperidine (0.460 mL,4.66 mmol), and glacial AcOH (0.160 mL, 2.80 mmol) in a dropwisefashion. The resulting yellow solution was stirred at 23° C. for 2 h,then treated with solid NaBH(OAc)₃ (393 mg, 1.86 mmol) in one portion,and stirring was continued for 14 h. After stirring 14 h at 23° C., themixture was treated with 2M K₂CO₃ (6 mL), and stirred for 1 h. After 1h, the mixture was diluted with EtOAc (50 mL) and washed with H₂O (1×50mL), and saturated NaCl (1×50 mL). The organic phase was then dried(MgSO₄) and concentrated in vacuo to provide the title compound as ayellow residue. The crude material was used in subsequenttransformations without further purification. MS m/z: 323 (M+H).

[0495] Preparation Y: 2-Amino-3-(1-piperidinylmethyl)-pyridine

[0496] 2-(Phthalimidyl)-3-(1-piperidinylmethyl)-pyridine (196 mg, 0.609mmol) was dissolved in EtOH (95%, 2 mL) at 23° C., and treated withhydrazine monohydrate (0.0320 mL, 0.670 mmol) in a dropwise fashion. Theresulting mixture was warmed to reflux and stirred for 3 h at reflux.The solution was treated with additional hydrazine monohydrate (0.150mL, 3.050 mmol), and reflux continued. After 14 h at reflux, the mixturewas cooled to RT, and concentrated using a rotary evaporator to a whitepaste. The resulting white paste was dissolved in CHCl₃:IpOH (3:1, 75mL), and washed with saturated NaHCO₃ (3×50 mL), and H₂O (1×50 mL). Theorganic layer was dried over MgSO₄ and concentrated in vacuo to providethe title compound as a white solid. MS m/z: 192 (M+H).

[0497] Preparation Z: N-Pivaloyl 2-amino-5-(bromomethyl) pyridine

[0498] N-Pivaloyl-2-amino-5-methylpyridine (5.12 g, 26.6 mmol) wasdissolved in CCl₄ (75 mL) at 23° C., and treated with NBS (9.69 g, 54.4mmol), followed by AIBN (937 mg, 5.71 mmol) with stirring. The resultingorange, biphasic suspension was then warmed to reflux for 4 h. After 4 hat reflux, the rust-colored mixture was cooled to RT, filtered through aCeliteo pad, and concentrated in vacuo to a red residue. Purificationover silica gel (gradient, 0 to 25% EtOAc/hexanes) provided the titlecompound as a light yellow solid. MS m/z: 272 (M+H).

[0499] Preparation AA:N-Pivaloyl-2-amino-5-[2-(N-tert-butoxycarbonyl)amino]ethoxymethylpyridine

[0500] N-Pivaloyl-2-amino-5-bromomethylpyridine (484 mg, 1.78 mmol) wasdissolved in THF (6 mL) at 23° C., and treated with2-(N-tert-butoxycarbonyl)aminoethanol (0.551 mL, 3.56 mmol), followed byNaH (60% suspension in mineral oil, 221 mg, 5.52 mmol) with stirring.The resulting mixture was stirred at 23° C. for 14 h, then treated withadditional NaH (75.6 mg, 1.89 mmol) as well as DMSO (1 mL), and stirredan additional 5 h at 23° C. After 5 h at 23° C., the solution was warmedto 55° C. for 3 h, then cooled to RT. The mixture was treated withsaturated NaHCO₃ (10 mL), diluted with EtOAc (50 mL), and washed withsaturated NaHCO₃ (2×50 mL). The mixture was dried over MgSO₄ andpurified over silica gel to provide the title compound as a pale yellowoil. MS m/z: 352 (M+H).

[0501] The following amines were prepared from the correspondingbromomethylpyridine in a manner similar to that described in GeneralPreparation AA:

[0502] 1]2,2-Dimethyl-N-(6-(N-(tert-butoxycarbonyl)-amino-1-ethoxymethyl)pyridin-2-yllpropionamide.MS m/z: 352 (M+H).

[0503] 2] N-Pivaloyl-2-amino-6-[(4-methylphenyl)-oxymethyl]pyridine. MSm/z: 299 (M+H).

[0504] 3] N-Pivaloyl-2-amino-5-[(4-methylphenyl)-oxymethyl]pyridine. MSm/z: 299 (M+H).

[0505] Preparation AB:N-Pivaloyl-2-amino-5-[1-morpholinylmethyl]pyridine

[0506] N-Pivaloyl-2-amino-5-bromomethylpyridine (478 mg, 1.76 mmol) wasdissolved in THF at 23° C. with stirring and treated with morpholine(0.770 mL, 8.81 mmol) in a dropwise fashion. The resulting brown mixturewas stirred at 23° C. for 14 h. After stirring 14 h, the mixture wastreated with saturated NaHCO₃ (2 mL) and stirred an additional 5 h at23° C. After 5 h, the brown mixture was warmed to 55° C. for 3 h, thencooled to RT and diluted with EtOAc (50 mL). The mixture was washed withsaturated NaHCO₃ (2×50 mL), dried (MgSO₄), and concentrated to a brownresidue which was immediately purified over silica gel (0 to 5%MeOH/CHCl₃) to provide the title compound as a yellow oil. MS m/z: 278(M+H).

[0507] Preparation AC: 2-(Butyloxycarbonyl)amino-6-methylpyridine

[0508] To a 2-L 3-neck Miller flask charged with2-amino-6-methylpicoline (15 g, 138.7 mmol) and dry THF (1 L) was addeddi-tert-butyl dicarbonate (33.3 g, 152.6 mmol) then TEA (21.2 mL, 152.6mmol) via addition funnel at 0° C. The reaction mixture was warmed to RTand added DMAP (1.7 g, 13.9 mmol). After 3.5 h, extracted with EtOAc,washed with saturated NH₄Cl, H₂O (3×), and brine (3×), dried (MgSO₄) andconcentrated in vacuo to afford the crude material as a turbid yellowoil. Trituration with hexane formed a precipitate which was filtered andthe filtrate was concentrated in vacuo to give the title compound as ayellow oil.

[0509] Preparation AD: 6-Bromomethyl-2-(butyloxycarbonyl)amino-pyridine

[0510] To a solution of N-Boc-2-amino-6-picoline (28.7 g, 138 mmol) andCCl₄ (500 mL) was added NBS (27.1 g, 151.8 mmol) and AIBN (2.3 g, 13.8mmol) and heated to reflux. After 2 h, added 0.1 equivalent of AIBN. Thereaction mixture was heated at reflux for 20 h, filtered andconcentrated in vacuo to give a dark oil. Purified by silica flashchromatography (100% hexane to 5% EtOAc/Hexane) to afford the desired asa yellow oil. MS m/z: 288.0 (M+H)

[0511] Preparation AZ: 2-(Butyloxycarbonyl)amino-6-cyanomethylpyridine

[0512] To a solution of N-Boc-2-amino-6-methylbromidepyridine (12 g,41.8 mmol) and EtOH (250 mL) was added NaCN (2 g, 41.8 mmol). Thereaction mixture was heated to reflux for 2 h then cooled to RT andconcentrated in vacuo. Purification by silica flash chromatography (100%Hexane to 20% EtOAc/Hexane) afforded the title compound as a yellow oil.MS m/z: 234.0 (M+H).

[0513] Preparation AF: 2-Amino-6-cyanomethylpyridine

[0514] To a solution of N-Boc-2-amino-6-methylnitrilepyridine and CH₂Cl₂(10 mL) was added TFA (8 mL) and stirred at RT. After 3 h, the mixturewas concentrated in vacuo, diluted with EtOAc and saturated NaHCO₃ wascarefully added. The mixture was washed with saturated NaHCO₃ (2×) andbrine, dried (MgSO₄) and concentrated in vacuo to afford the titlecompound as a yellow solid.

[0515] Preparation AG: 6-Aminoethyl-2-(butyloxycarbonyl)amino-pyridine

[0516] A solution of N-Boc-2-amino-6-methylnitrile-pyridine (1 g, 4.3mmol) and EtOH (25 mL) was hydrogenated over 20% Pd(OH)₂/C at RT and 40psi. After 18 h, the mixture was filtered through Celite® and elutedwith EtOAc. The filtrate was concentrated in vacuo to afford the titlecompound as a white foamy solid.

[0517] Preparation AH: 2-Amino-6-(phthalimidyl)ethyl-pyridine

[0518] To a solution of N-Boc-2-amino-6-ethylaminopyridine (1 g, 4.3mmol) and CHCl₃ (25 mL) was added phthalic anhydride (0.64 g, 4.3 mmol).Heated to 70° C. for 15 h then at RT for 5 days. The mixture was washedwith H₂O and brine, dried (MgSO₄) and concentrated in vacuo to givecrude N-Boc-2-amino-6-ethylphthalamidylpyridine, which was used withoutfurther purification. To a solution of crudeN-Boc-2-amino-6-ethylphthalamidylpyridine (1.6 g, 4.3 mmol) and CH₂Cl₂(10 mL) was added 10 mL of TFA and the mixture was stirred at RT. After30 min, the mixture was concentrated in vacuo. The residue was dilutedwith 90% MeOH/CH₂Cl₂ and treated with solid NaHCO₃, stirred for 15 minthen filtered. The filtrate was concentrated in vacuo to afford thetitle compound as a yellow solid. MS m/z: 268.2 (M+H).

[0519] Preparation AI: 2-[(6-Bromopyridin-2-yl)methylamino]-propan-1-ol

[0520] To a stirred solution of the (6-bromo-2-pyridyl)-formaldehyde(0.52 g, 2.8 mmol) in toluene (14 mL) was added DL-2-amino-1-propanol(0.67 mL). The resulting mixture was heated to reflux with a Dean-Starktrap for 3 h under N₂ until complete formation of the imine wasobserved. The mixture was brought to RT followed by the addition of asolution of NaBH(OAc)₃ (2.0 g, 9.8 mmol) in ACOH (6 mL). The resultingmixture was stirred at RT and under N₂ for 56 h. The mixture wasneutralized (pH 7.0) with a saturated solution of NaHCO₃ (aq) andextracted with CH₂Cl₂ (3×50 mL). The aqueous layer was concentrated byrotary evaporation and the residue obtained was extracted with CH₂Cl₂(3×50 mL). The organic layers were combined, dried over MgSO₄, filteredand concentrated by rotary evaporation to afford the title compound as apale yellow oil. EI-MS m/z 245 (M+H).

[0521] Preparation AJ:(tert-Butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-(2-hydroxy-isopropyl)carboxamide

[0522] To a stirred solution of2-[(6-bromo-2-pyridyl)-methyl]aminopropan-1-ol (0.55 g, 2.2 mmol) in dryCH₂Cl₂ (11 mL) was added Boc₂O (0.51 g, 2.42 mmol) . The resultingmixture was stirred at RT and under N₂ for 15 h. The mixture wasconcentrated by rotary evaporation and purified on silica gel (2:1hexanes/EtOAc, 5:95 MeOH/CH₂Cl₂ and, 10:90 MeOH/CH₂Cl₂) as eluent toafford the title compound as an off-white oil. EI-MS m/z 345 (M+H).

[0523] Preparation AK:(tert-Butoxy-N-[(6-bromo(2-pyridyl))-methyl]-N-(1-methyl-2-oxoethyl)carboxamide

[0524] To a dry flask was added oxalyl chloride (72 μL) followed by theaddition of dry CH₂Cl₂ (2 mL). The resulting colorless solution wasbrought to −63° C. (dry ice/CHCl₃) and a solution of DMSO (80 μL) in 0.5mL dry CH₂Cl₂ was slowly added dropwise. A solution of(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-(2-hydroxy-isopropyl)carboxamide(0.19 g, 0.55 mmol) in dry CH₂Cl₂ (2 mL), was added slowly drop wise.The resulting mixture was kept at −63° C. and stirred for 30 min,followed by the slow addition of a solution of TEA (0.31 mL) in dryCH₂Cl₂ (1 mL) . The mixture was stirred at −63° C. until all thestarting material was consumed (checked by MS). The mixture was broughtto −20° C., quenched with a saturated solution of NH₄Cl (aq) and dilutedwith EtOAc. The organic phase was separated and the aqueous phase wasextracted with EtOAc (3×20 mL). The organic layers were combined, driedover MgSO₄, filtered and concentrated by rotary evaporation to affordthe title compound as a pale yellow semi-solid. EI-MS m/z 343 (M+H).

[0525] Preparation AL:N-[2-(diethylamino)-isopropyl](tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-carboxamide

[0526] To a stirred solution of(tert-butoxy-N-[(6-bromo(2-pyridyl))methyl]-N-(1-methyl-2-oxoethyl)-carboxamide(0.15 g, 0.44 mmol) in toluene (3 mL) was added DEA (0.2 mL). Theresulting mixture was heated to reflux in a Dean-Stark trap under N₂ for3 h. The mixture was brought to RT followed by the addition of asolution of NaBH(OAc)₃ (0.33 g, 1.54 mmol) in AcOH (6 mL). Theyellow-solution was stirred at RT and under N₂ for 15 h. The mixture wasdiluted with EtOAc (20 mL) and washed with a saturated solution ofNaHCO₃ (aq) (50 mL). The organic phase was separated, dried (MgSO₄),filtered and concentrated by rotary evaporator to afford the titlecompound as a brown/yellow oil. EI-MS m/z 400 (M+H).

[0527] Preparation AM:N-[2-(diethylamino)isopropyl](tert-butoxy)-N-[(6-amino(2-pyridyl))methyl]-carboxamide

[0528] To a stirred solution ofN-[2-(diethylamino)-isopropyl)(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-carboxamide(80 mg 0.2 mmol) in IpOH (4 mL) in a sealed tube, was added NH₄OH(28-30%, 6 mL) followed by an excess of Cu. The resulting solution washeated under pressure at 90° C. for 24 h. The mixture was brought to RT,diluted with H₂O (20 mL) and extracted with CHCl₃ (3×20 mL). The organiclayers were combined, dried over MgSO₄, filtered and concentrated byrotary evaporation to afford the title compound as a pale-yellow oil.EI-MS m/z 337 (M+H).

[0529] Preparation AN: Methyl2-[(6-bromo-2-pyridylmethyl)amino]-3-methyl-butyrate

[0530] To a stirred solution of L-valine methyl ester hydrochloride(0.54 g, 3.24 mmol) in dry toluene (15 mL) at 80° C. was added DIEA (2.0mL 11 mmol) followed by (6-bromo-2-pyridyl)formaldehyde (0.50 g, 2.70mmol). The resulting mixture was heated at 80° C. for 3 h. The reactionwas brought to RT and a solution of NaBH(OAc)₃ (1.4 g, 6.75 mmol) inglacial AcOH (4 mL) was added. The resulting mixture was stirred for 15h and concentrated by rotary evaporation. The resulting yellow oil wasdissolved in CH₂Cl₂ (100 mL), washed with a saturated solution of NaHCO₃(aq) (50 mL), brine (50 mL), dried over Na₂SO₄, filtered, concentratedby rotary evaporation and purified by flash chromatography (2:1hexanes/EtOAc) to afford the title compound as a pale-yellow oil. EI-MSm/z 301 (M+H).

[0531] Preparation AO:2-[(6-Bromo-2-pyridylmethyl)amino]-3-methyl-butanol

[0532] To a stirred solution of(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-[2-oxomethoxide-1-(methylethyl)-ethyl]carboxamide(0.47 g, 1.57 mmol) in dry toluene (25 mL) at −78° C. was added dropwiseDIBAL-H (1.0 M solution in hexane, 4.7 mL). The resulting brown-solutionwas stirred at −78° C. for 3 h, brought to RT and stirred until startingmaterial was consumed. The organic layer was separated, dried overNa₂SO₄, filtered, concentrated by rotary evaporation and purified onsilica gel (10:90 MeOH/CH₂Cl₂) to afford the title compound as a yellowoil. EI-MS m/z 273 (M+H).

[0533] Preparation AP: tert Butyl(6-bromopyridin-2-ylmethyl)-(1hydroxymethyl-2-methyl-propyl)-carbamate

[0534] To a stirred solution of2-[(6-bromo-2pyridylmethyl)amino]-3-methyl-butanol (0.30 g, 1.10 mmol)in CH₂Cl₂ (5 mL) was added Boc₂O (0.26 g, 1.21 mmol). The resultingsolution was stirred for 15 h, concentrated by rotary evaporation andpurified on silica gel (5:95 MeOH/CH₂Cl₂ and 10:90 MeOH/CH₂Cl₂) toafford the title compound as a pale yellow solid. EI-MS m/z 373 (M+H).

[0535] Preparation AQ: tert Butyl(6-bramopyridin-2-ylmethyl)-(1-formyl-2-methyl-propyl) carbamate

[0536] To a flame-dried flask was added oxalyl chloride (70 μL) followedby the addition of dry CH₂Cl₂ (2 mL). The resulting colorless solutionwas brought to −63° C. (dry ice/CHCl₃) and a solution of DMSO (70 μL) in0.5 mL dry CH₂Cl₂ was slowly added drop wise. The(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-[2-hydroxy-1-(methylethyl)ethyl]carboxamide(0.19 g, 0.51 mmol), previously dissolved in dry CH₂Cl₂ (2 mL) , wasadded slowly dropwise. The resulting mixture was kept at −63° C. andstirred for 30 min followed by the slowly addition of a solution of TEA(0.3 mL) in dry CH₂Cl₂ (1 mL). The mixture was stirred at −63° C. untilall the starting material was consumed (checked by MS) (1.5 h). Themixture was brought to −20° C., quenched with a saturated solution ofNH₄Cl (15 mL) and diluted with EtOAc (35 mL). The organic phase wasseparated and the aqueous phase was extracted with EtOAc (3×30 mL). Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated by rotary evaporation without further purification toafford the title compound as a yellow-semi solid. EI-MS m/z 371 (M+H).

[0537] Preparation AR: tert-Butyl(6-bromopyridin-2-ylmethyl)-(1-diethylaminomethyl-2-methyl-propyl)carbamate

[0538] To a stirred solution of(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]-N-[1-(methylethyl)-2-oxoethyl]carboxamide(0.17 g, 0.46 mmol) in toluene (5 mL) was added DEA (0.14 mL). Theresulting mixture was heated to reflux in a Dean-Stark trap under N₂ for3 h. The mixture was brought to RT followed by the addition of asolution of NaBH(OAc)₃ (0.34 g, 1.61 mmol) in glacial AcOH (6 mL). Theyellow-solution was stirred at RT and under N₂ for 15 h. The mixture wasdiluted with EtOAc (20 mL) and washed with a saturated solution ofNaHCO₃ (aq) (15 mL). The aqueous layer was separated and concentratedunder reduced pressure. The solid obtained was extracted with CH₂Cl₂.The extracts were combined, dried over MgSO₄, filtered and, concentratedby rotary evaporation to afford the title compound as a pale yellow oil.EI-MS m/z 428 (M+H).

[0539] Preparation AS: tert-Butyl(6-aminopyridin-2-ylmethyl)-(1-diethylaminomethyl-2-methyl-propyl)carbamate

[0540] To a stirred solution ofN-{1-[(diethylamino)-methyl]-2-methylpropyl}(tert-butoxy)-N-[(6-bromo(2-pyridyl))methyl]carboxamide(5 mg, 0.012 mmol) in IpOH (5 mL) in a sealed tube, was added NH₄OH(28-30% 6 mL) followed by excess Cu. The resulting solution was heatedunder pressure at 90° C. for 24 h. The mixture was brought to RT,diluted with H₂O (10 mL) and extracted with CHCl₃ (3×20 mL) The organiclayers were combined, dried over MgSO₄, filtered and concentrated byrotary evaporation to afford the title compound as a green oil. Nopurification was required. EI-MS m/z 365 (M+H).

[0541] Preparation AT: 2-Bromo-6-(piperidin-1-ylmethyl)pyridine

[0542] To a stirred solution of 6-bromo-2-pyridine carboxaldehyde (5.05g, 27 mmol) in anhydrous CH₂Cl₂ (200 mL) at RT, under N₂, piperidine(2.95 mL, 29 mmol) was added, followed by NaBH(OAc)₃ (11.51 g, 54 mmol)and AcOH (6.2 mL, 108 mmol) 30 min later. After 20 h, a 2M solution ofNa₂CO₃(aq) (20 mL) was added. The mixture was vigorously stirred for anadditional 30 min, washed successively with a saturated solution ofNaHCO₃(aq) until the pH of the aqueous layer reached 7 (2×100 mL), H₂O(100 mL) and brine (100 mL). The organic layer was separated, dried overMgSO₄, filtered and concentrated under reduced pressure to yield thetitle compound as a yellow oil. This was used crude in the next step. MSm/z: 255 (M+H), 257 (M+3).

[0543] Preparation AU: 2-Amino-6-(piperidin-1-ylmethyl)pyridine

[0544] To a solution of 2-bromo-6-(piperidylmethyl)pyridine (5.21 g, 20mmol) in IpOH (30 mL) in a sealed tube at RT, a catalytic amount of Cu(100 mg) and 28-30% NH₄OH (35 mL) were added. The stirred suspension washeated to 95° C. for 40 h. After cooling to RT, the reaction mixture wasdiluted with H₂O (100 mL) and extracted with EtOAc (4×80 mL)). Theorganic layers were combined, then washed with H₂O (50 mL) followed bybrine (50 mL). The organic layer was separated, dried over Na₂SO₄,filtered and concentrated under reduced pressure to yield the titlecompound as a dark yellow oil. This was used as crude. MS m/z: 193(M+H)+.

[0545] Preparation AV: Ethyl 2-(4-aminosulfonylphenyl)thiazole-4-carboxylate

[0546] In an oven-dried, 100-mL, round-bottomed flask were placed4-cyanobenzenesulphonamide (4.1 g, 22.50 mmol), TEA (5 mL) in pyridine(40 mL). H₂S was bubbled through this mixture for 1 h at RT. Thereaction was diluted with EtOAc (125 mL) and H₂O (50 mL). The phaseswere separated, and the organic layer was washed with H₂O (4×25 mL) andbrine (15 mL), dried over MgSO₄, and concentrated in vacuo to afford thecrude thiobenzamide as an oily solid; MS m/z: 217 (M+H). In anoven-dried, 100-mL, round-bottomed flask were placed the crudethiobenzamide, ethyl bromopyruvate (3.0 mL, 23.66 mmol) in EtOH (40 mL).The reaction was heated to 75° C. for 12 h, then cooled to RT. Themixture was concentrated in vacuo to give the crude sulfonamide as ayellow solid which was filtered, washed with H₂O (1×10 mL) and Et₂O(4×10 mL) to afford the title compound as a yellow solid. MS m/z: 313(M+H).

[0547] Preparation AW: 2-(4-Aminosulfonylphenyl)thiazole-4-carboxylicacid

[0548] In an oven-dried, 100-mL, round-bottomed flask was placed ethyl2-(4-aminosulfonylphenyl)thiazole-4-carboxylate (1300 mg, 4.2 mmol),LiOH monohydrate (350 mg, 8.3 mmol) in MeOH (40 mL) and H₂O (4 mL). Thesolution was heated to 75° C. for 3 h, cooled to RT, and concentrated.The resulted yellow solid was dissolved in H₂O (10 mL), extracted withEtOAc (1×15 mL). The aqueous layer was acidified with 2N aqueous HCl(4.15 mL). The precipitate was filtered, and washed with H₂O (10 mL) toafford the title compound as a light-yellow solid. MS m/z: 285 (M+H).

[0549] Preparation AX:2-(4-(4-morpholinyl)sulfonylphenyl)thiazole-4-carboxylic acid

[0550] In a manner similar to that described for the preparation of2-(4-aminosulfonylphenyl)thiazole-4-carboxylic acid, 460 mg of4-(morpholinosulfonyl)-benzonitrile was treated with H₂S, ethylbromopyruvate, and LiOH successively to give the title compound. MS m/z:355 (M+H).

[0551] Preparation AY: 2-(4-Boc-aminophenyl)-thiazole-4-carboxylic acid

[0552] In a manner similar to that described for the preparation of2-(4-aminosulfonylphenyl)thiazole-4-carboxylic acid,4-[(1,1-dimethylethoxy)carbonyl]aminobenzonitrile was treated with H₂S,ethyl bromopyruvate, and LiOH successively to give the title compound.MS m/z: 321 (M+H).

[0553] Preparation AZ: Ethyl 2-(phenoxy)thiazole-4-carboxylate

[0554] A mixture of the bromothiazole (1.03 g, 4.36 mmol) and phenol(10.0 g, 106 mmol) was stirred at 180° C. for 1 h, cooled to RT, dilutedwith 100 mL of EtOAc, washed with 1N NaOH (40×3), H₂O, and brine, thendried over MgSO₄, and concentrated in vacuo to yield a light yellowresidue. Purification over silica gel (gradient, 5% to 10%EtOAc/hexanes) provided the title compound. MS m/z: 250 (M+H)+⁺.

[0555] Preparation BA: 2-(Phenoxy)thiazol-4-ylcarbonylazide

[0556] TEA (0.17 mL, 1.20 mmol) was added to a solution of the thiazolecarboxylic acid (0.13 g, 0.59 mmol) in 10 mL of THF at 0° C. The mixturewas stirred at 0° C. for 20 min whereupon ethyl chloroformate (0.065 mL,0.65 mmol) was added. After the mixture was stirred for 30 min, asolution of NaN₃ (0.043 g, 0.65 mmol) in 3 mL of H₂O was added, thereaction was stirred for 30 min, then warmed to RT, diluted with 25 mLof H₂O, and extracted with EtOAc. The combined organic portions werewashed with brine, dried over MgSO₄, filtered, and removal of thesolvents in vacuo yielded the title compound as a light brownish solid.MS m/z: 247 (M+H).

[0557] Preparation BB: 6-Chloro-thionicotinamide

[0558] To a solution of the 4-chloronicotinamide (5 g, 31.9 mmol) anddry THF (200 mL) was added P₂S₅ (15.6 g, 35.1 mmol) and Na₂CO₃ (3.7 g,35.1 mmol). The mixture was heated at reflux for 1.5 h, cooled andfiltered off a yellow solid. The filtrate was extracted with EtOAc,washed with H₂O and brine; dried (MgSO₄) then concentrated in vacuo togive the title compound as a yellow solid. MS m/z: 173.0 (M+H).

[0559] Preparation BC: Ethyl2-(6-chloro-3-pyridyl)thiazole-4-carboxylate

[0560] To a mixture of the 4-chloro-thionicotinamide (5.5 g, 31.9 mmol)and EtOH (300 mL) was added bromo-ethyl-pyruvate (4.4 mL, 35.1 mmol).The mixture was heated at reflux for 15 h, cooled and concentrated invacuo to afford a yellow solid/orange oil. The oil was diluted withEtOAc and filtered off yellow solid. The filtrate was filtered throughCelite® and concentrated in vacuo to give a dark yellow oil. The oil wasdiluted with 2% MeOH/CH₂Cl₂ and filtered through a pad of silica gel(150 mL). Elution with 2% MeOH/CH₂Cl₂ (500 mL), followed byconcentration in vacuo afforded the title compound as a yellowcrystalline solid. MS m/z: 269.1 (M+H).

[0561] Preparation BD: 2-(6-Methoxy-3-pyridyl)thiazole-4-carboxylic acid

[0562] To a solution of the ethyl2-(6-chloro-3-pyridyl)thiazole-4-carboxylate (0.61 g, 2.3 mmol) and MeOH(50 mL) was added solid NaOMe (135 mg, 2.5 mmol) and stirred at RT.After 3 h the ethyl ester transesterified to the methyl ester. NaOMe (1eq, 135 mg) was added and the mixture was heated to reflux. After 15 h,the ester hydrolyzed to the 2-(6-chloro-3-pyridyl)thiazole carboxylicacid. NaOMe (2 eq) was added and the reaction was heated at reflux for18 h. The mixture was acidified to pH 5 with concentrated HCl, extractedwith EtOAc, washed with H₂O and brine; dried (MgSO₄) and concentrated invacuo to give the desired carboxylic acid as a yellow solid. MS m/z:237.1 (M+H).

[0563] Preparation BE: 2-(2-Chloropyridin-4-yl)thiazole-4-carbonyl azide

[0564] A mixture of 3-(3-chloro-4-pyridyl)-4-thiazole carboxylic acid(0.6 g, 2.5 mmol) and dry THF (20 mL) was cooled to 0° C. with stirring.TEA (0.7 mL, 5.0 mmol) was added and the reaction mixture was stirredfor 20 min. Ethyl chloroformate (0.24 mL, 2.5 mmol) was added and thesolution was stirred for 30 min. A solution of NaN₃ (174 mg, 2.7 mmol)in 3 mL of H₂O was added and the reaction mixture was warmed to RT.After 30 min, 10 mL of H₂O was added and the mixture was extracted withEtOAc (3×), dried (MgSO₄) and concentrated in vacuo to give the titlecompound as a pink solid. MS m/z: 266.0 (M+H)+

[0565] Preparation BF: Ethyl 2-(3-methoxyphenyl)-thiazole-4-carboxylate

[0566] A suspension of 3-methoxyphenyl boronic acid (0.25 g, 1.65 mmol),ethyl 2-bromothiazole-4-carboxylate (0.33 g, 1.4 mmol), PdCl₂(dppf)₂(0.11 g) and 2M Na₂CO₃ (aq) (2 mL) in DME (10 mL) was heated to refluxfor 20 h. The mixture was cooled to RT, filtered, concentrated by rotaryevaporation and purified on silica gel (6:1 hexanes/EtOAc and 4:1hexanes/EtOAc) to afford the title compound as a light-brown oil. EI-MSm/z 264 (M+H).

[0567] Preparation BG: 2-(3-Methoxyph nyl)thiazole-4-carboxylic acid

[0568] To a stirred solution of the ethyl2-(3-methoxyphenyl)thiazole-4-carboxylate (0.23 g, 0.87 mmol) in EtOH(10 mL) was added 1N NaOH (aq) (5 mL). The resulting mixture was heatedto reflux until the starting material was consumed (2 h). The mixturewas cooled to RT, acidified with 1N HCl (aq) and concentrated by rotaryevaporation. The residue was extracted with CH₂Cl₂ (3×15 mL). Theextracts were combined, dried over MgSO₄, filtered and concentrated byrotary evaporation to afford the title compound as an off-white solid.EI-MS m/z 236 (M+H).

[0569] Preparation BH: Ethyl 2-(2-methoxyphenyl)-thiazole-4-carboxylate

[0570] A suspension of 2-methoxyphenyl boronic acid (0.25 g, 1.65 mmol),ethyl 2-bromothiazole-4-carboxylate (0.33 g, 1.4 mmol), PdCl₂(dppf)₂(0.11 g, 0.14 mmol) and 2M Na₂CO₃(aq) (2 mL) in DME (10 mL) was heatedat reflux for 20 h, cooled to RT, filtered, concentrated by rotaryevaporation and purified on silica gel (6:1 hexanes/EtOAc and 4:1hexanes/EtOAc) to afford the title compound as a light-brown oil. EI-MSm/z 264 (M+H).

[0571] Preparation BI: 2-(2-Methoxyphenyl)thiazole-4-carboxylic acid

[0572] To a stirred solution of ethyl2-(2-methoxyphenyl)thiazole-4-carboxylate (0.27 g, 1.03 mmol) in EtOH(10 mL) was added 1N NaOH (aq) (5 mL). The resulting mixture was heatedto reflux for 2 h. The mixture was cooled to RT, acidified with 1N HCl(aq) and concentrated by rotary evaporation. The residue was extractedwith CH₂Cl₂ (3×15 mL). The extracts were combined, dried over MgSO₄,filtered and concentrated by rotary evaporation to afford the titlecompound as an off-white solid. EI-MS m/z 236 (M+H).

[0573] Preparation BJ: 2-[(4-Methoxyphenoxy)methyl]thiazole-4-carboxylicacid

[0574] To a stirred solution of ethyl2-(4-methoxyphenoxy)methyllthiazole4-carboxylate (0.10 g, 0.34 mmol) inEtOH (5 mL) was added 1N NaOH (2.0 mL) and was heated to reflux untilthe starting material was consumed (2 h). The mixture was brought to RT,acidified with 1N HCl (pH 4.0) and concentrated by rotary evaporation.The residue obtained was partitioned between EtOAc (50 mL) and H₂O (30mL). The organic phase was separated, dried over MgSO₄, filtered andconcentrated by rotary evaporation to afford the title compound as awhite solid. EI-MS m/z 266 (M+H).

[0575] Preparation BK: 2-Amino-thiazole-4-carboxylic acid ethyl esterhydrobromide

[0576] To a stirred suspension of thiourea (24.26 g, 0.319 mol) in 200proof EtOH (350 mL) at RT, under N₂, ethyl bromopyruvate (62.16 g, 0.319mol) was added dropwise. Upon completion the yellow solution was heatedto 45° C. for 15 h, then placed in a fridge overnight. The precipitatewas filtered off and washed with cold EtOH (3×100 mL) to yield the titlecompound as a pale yellow amorphous solid. MS m/z: 173.1 (M+H), 195.1(M+Na). Calc'd. for C₆H₉BrN₂O₂S—253.12.

[0577] Preparation BL: 2-Bromothiazole-4-carboxylic acid

[0578] To a well stirred suspension of ethyl2-aminothiazole-4-carboxylate hydrobromide (29.99 g, 0.17 mol) in 16%HBr(aq) (400 mL) at 0° C., a solution of NaNO₂ (12.49 g, 0.18 mol) inH₂O (22 mL) was added dropwise. The mixture was maintained at 0° C. foran additional 35 min then CuBr (28.23 g, 0.20 mol) and an additionalvolume of 16% HBr(aq) (150 mL) were added. The ice bath was removed andthe suspension heated to 70° C. for 1 hr. The mixture was filtered hot.The filtrate was saturated with NaCl then extracted with EtOAc (2×400mL). The combined organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude brown oil/solid residuewas used directly in the next step. A solution of the brown residue inEtOH (100 mL) and 1M NaOH (aq) (367 mL, 0.36 mol) was stirred and heatedat reflux for 1 h. The reaction mixture was filtered then extracted withEtOAc (100 mL). The aqueous layer was separated and concentrated underreduced pressure to remove the remaining EtOH. The aqueous solution wasacidified to pH 1 with 2N HCl(aq). The solid was filtered off and airdried to yield the title compound as a beige amorphous solid. MS m/z:208 (M+H) 210 (M+3).

[0579] Preparation BM: Ethyl2-(2,6-dichloro-4-pyridyl)thiazole-4-carboxylate

[0580] 2,6-Dichloropyridine-4-thiocarboxamide (1.0 g, 4.83 mmol) wasdissolved in dry 1,4-dioxane followed by adding ethyl bromopyruvate (0.9mL, 7.24 mmol) and pyridine (0.4 mL, 4.83 mmol). The resulting mixturewas heated to reflux under N₂ for 5 h. After cooling to RT, solvent wasremoved. The residue was extracted with CHCl₃. The organic layer waswashed with H₂O and brine, dried over MgSO₄, and concentrated to give abrownish solid. This crude was purified by chromatography on silica gel.Elution with hexane:acetone (90:10) gave a title compound as yellowsolid. MS m/z: 303 (M+H). Calc'd. for C₁₁H₈Cl₂N₂O₂S—303.16.

[0581] Preparation BN: 2-(2,6-Dichloro-4-pyridyl)thiazole-4-carboxylicacid

[0582] 2-(2,6-Dichloropyridin-4-yl)-ethylthiazolo-4-carboxylate (500 mg,1.65 mmol) was dissolved in MeOH (10 mL) followed by adding 1N NaOH (2.5mL, 2.47 mmol). The resulting mixture was stirred at RT for 4 h. The pHwas adjusted to 5 using 1N HCl. The solvent was removed in vacuo and theresidue was partitioned between EtOAc and H₂O. The aqueous layer wasextracted more with EtOAc. The combined organic layers was dried overMgSO₄ and concentrated to give a white solid. MS m/z: 275.1 (M+H).Calc'd. for C₉H₄Cl₂N₂O₂S—275.11.

[0583] Preparation BO: Ethyl6-[2-(2,2,2-trifluoroethoxy)-3-pyridyllthiazole-4-carboxylate

[0584] 6-(2,2,2-Trifluoroethoxy)pyridine-3-thiocarboxamide (800 mg, 3.4mmol), ethyl bromopyruvate (0.9 mL, 6.8 mmol), and pyridine (0.3 mL, 3.4mmol) were heated at reflux in dry 1,4-dioxane (20 mL) to yield titlecompound as pale yellow solid. MS m/z: 333.1 (M+H). Calc'd. forC₁₃H₁₁F₃N₂O₃S—332.3.

[0585] Preparation BP:6-[2-(2,2,2-trifluoroethoxy)-3-pyridyllthiazole-4-carboxylic acid

[0586] Ethyl6-[2-(2,2,2-trifluoroethoxy)-3-pyridyl]thiazole-4-carboxylate (750 mg,2.25 mmol) and 1N NaOH (3.4 mL, 3.4 mmol) were dissolved in MeOH (10 mL)to afford the title compound as a white solid. MS m/z: 305.1 (M+H).Calc'd. for C₁₁H₇F₃N₂O₃S—304.25.

[0587] Preparation BQ: 2-(Phenoxy)thiazole-4-carboxylic acid

[0588] A mixture of ethyl 2-phenoxythiazole-4-carboxylate (0.17 g, 0.68mmol) and LiOH monohydrate (0.14 g, 3.40 mmol) in 2 mL of MeOH, 2 mL ofH₂O, and 2 mL of THF was stirred at RT overnight, the solvents wereremoved in vacuo and the residue was diluted with water. The aqueousmixture was acidified with 1N HCl (aq) to pH=1-2, then extracted withEtOAc, the combined organic portions were washed with brine, dried overMgSO₄, filtered, removal of the solvents in vacuo yielded the titlecompound as a white solid. EI-MS =222.4 (M+H)+. Calc'd for C₁₀H₇NO₃S:221.01.

[0589] Preparation BR: 3-(3-Nitrophenyl)pyridine

[0590] To a 1-iodo-3-nitrobenzene (1.0 g, 4.01 mmol) in dry DME (20 mL)was added pyridine-3-boronic acid (641 mg, 5.22 mmol), PdCl₂dppf (327mg, 0.40 mmol), and 2M Na₂CO₃ (3.0 mL). The resulting mixture was heatedto reflux under N₂ for 15 h. Solvent was separated from inorganic solidby filtration. The solvent was removed and the residue was extractedwith CHCl₃. The organic layer was washed with water, brine, and driedover MgSO₄. The solvent was removed to give dark brown solid which waspurified by chromatography on silica gel. Elution with Hexane:acetonemixture (80:20) gave the final compound as a tan solid. MS m/z: 201.3(M+H). Calc'd. for C₁₁H₈N₂O₂—200.23.

[0591] Preparation BS: 3-(3-Aminophenyl)pyridine

[0592] To a pre-hydrogenated solution of Pd(OH)₂ (298 mg, 2.12 mmol) inEtOH (10 mL) was added 3-(3-pyrid-1-yl)-1-nitrobenzene (440 mg, 2.12mmol) in EtOH (10 mL). The resulting mixture was stirred at RT under H₂for 2 h. Solvent was separated from Pd(OH)₂ by filtration throughCelite®. Solvent was then removed to give final compound as pale yellowsolid. MS m/z: 171.3 (M+H). Calc'd. for C₁₁H₁₀N₂—170.22.

[0593] Preparation BT:2,2-Dimethyl-N-[6-(2,2,6,6-tetramethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-propionamide:

[0594] 2,2,6,6-Tetramethylpiperidine (0.17 mL, 1.0 mmol) was added to asolution of N-pivaloyl-2-amino-6-bromomethylpyridine (180 mg, 0.66 mmol;M. Papadopoulou, et al., J. Het. Chem., 1995, 32, 675-681) in DMF (10mL) at 25° C. and the resulting mixture was stirred for 12 h. Thereaction mixture was partitioned between H₂O (15 mL) and EtOAc (20 mL)and the organics collected. The organics were washed with H₂O (20 mL)followed by brine (20 mL) and dried over MgSO₄. Concentration in vacuogave a colorless oil. MS m/z: 330.1 (M−H). Calc'd for C₂₀H₃₃N₃O—331.50.

[0595] Preparation BU:6-(2,2,6,6-Tetramethyl-piperidin-1-ylmethyl)-pyridin-2-ylamine:

[0596] KOH (1.68 g, 33.5 mmol) in MeOH (100 mL) was added to2,2-dimethyl-N-[6-(2,2,6,6-tetramethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-propionamide(150 mg, 0.45 mmol) and the resulting mixture was heated at reflux for12 h. After cooling to 25° C., the mixture was neutralized to pH 7-8with concentrated HCl and extracted with CHCl₃ (3×75 mL). The organicswere combined and dried over MgSO₄. Concentration in vacuo gave a paleyellow solid. MS m/z: 247.7 (M+). Calc'd for C₁₅H₂₅N₃—247.38.

[0597] Preparation BV: (2-Chloro-pyridin-4-yl)-piperidin-1-yl-methanone

[0598] To 2-chloroisonicotinic acid (1.0 g, 6.35 mmol) in dry CH₂Cl₂ (50mL) was added piperidine (1.3 mL, 12.69 mmol), DIEA (2.2 mL, 12.69mmol), HATU (1.2 g, 3.17 mmol), and EDCI (1.3 g, 6.98 mmol). The mixturewas stirred under N₂ at RT for 15 h. Solvent was removed and the crudecompound was purified by chromatography on silica gel. Elution withhexane:acetone mixture (80:20) gave a white solid. MS m/z: 225.1 (M+H).Calc'd. for C₁₁H₁₃ClN₂O—224.07.

[0599] Preparation BW: (2-Amino-pyridin-4-yl)-pip ridin-1-yl-methanon

[0600] NH₄OH (25 mL) and Cu powder (100 mg) were added to a solution of(2-amino-pyridin-4-yl)-piperidin-1-yl-methanone (1.0 g, 4.45 mmol) inIpOH (15 mL) and the mixture was heated at 100° C. for 48 h in a sealedtube. After cooling to RT, the mixture was partitioned between H₂O andCHCl₃. The aqueous layer was extracted with more CHCl₃ (3×20 mL). Thecombined organic layers was washed with brine, and dried over MgSO₄.Concentration in vacuo gave a light brown solid. MS m/z: 206.3 (M+H).Calc'd. for C₁₁H₁₅N₃0—205.12.

[0601] Preparation BX: 4-Piperidin-1-ylmethyl-pyridin-2-ylamine

[0602] To a stirred solution of(2-amino-pyridin-4-yl)piperidin-1-yl-methanone (100 mg, 0.487 mmol) indry THF (10 mL) at 0° C. was added LAH (1.5 mL, 1.46 mmol) dropwise. Themixture was heated to reflux for 20 h. The resulting mixture was cooledto 0° C. and quenched with H₂O (1.5 mL) dropwise followed by 10% NaOH(1.5 mL). Solvent was removed and the residue was partitioned betweenH₂O and CHCl₃. The organic layer was washed with H₂O, brine, dried overMgSO₄. Concentration in vacuo gave a light brown liquid. MS m/z: 192.2(M+H). Calc'd. for C₁₁H₁₇N₃—191.14.

[0603] Preparation BY: 4-Diethylaminomethyl-pyridin-2-ylamine

[0604] Prepared in a manner similar to that described for4piperidin-1-ylmethyl-pyridin-2-ylamine. MS m/z: 180.2 (M+H). Calc'd.for C₁₀H₁₇N₃—179.14.

[0605] Preparation BZ:[6-(2,6-Dimethyl-piperidin-1-ylmethyl)pyridin-2-yl]-carbamic acidtert-butyl eater

[0606] 2,6-Dimethylpiperidine (0.24 mL, 1.74 mmol) was added to asolution of (6-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester(250 mg, 0.87 mmol) in DMF (10 mL) followed by heating at 50° C. and theresulting mixture was stirred for 18 h. The resulting mixture waspartitioned between water (10 mL) and CHCl₃ (20 mL). The organic layerwas washed with H₃O, brine, and dried over MgSO₄. Concentration in vacuogave a pale yellow solid. MS m/z: 320.3 (M+H). Calc'd. forC₁₈H₂₉N₃O₂—319.23.

[0607] Preparation CA:6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-ylamine

[0608] HCl (1.25 mL, 1.25 mmol) in MeOH (15 mL) was added to[6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]carbamic acidtert-butyl ester (200 mg, 0.63 mmol) followed by heating at 40° C. for18 h. The resulting mixture was cooled to RT and basified to pH 9 with 2N NaOH. The mixture was extracted with CHCl₃ (3×20 mL). The combinedorganic layers was dried over MgSO₄ and concentrated in vacuo to give ayellow oil. MS m/z: 220.2 (M+H). Calc'd. for C₁₃H₂₁N₃—219.17.

[0609] Preparation CB: 1-(6-Bromo-pyridin-2-yl)-ethanol

[0610] 6-Bromo-2-pyridine carboxaldehyde (1.0 g, 5.37 mmol) in dry THF(20 mL) was cooled to −78° C. followed by adding MeMgI (2.0 mL, 5.91mmol) dropwise via the addition funnel. The cooling bath was removed.The resulting mixture was stirred for 1 h then quenched with sat. NH₄Cl.Solvent was removed. The residue was partitioned between water andCHCl₃. The organic layer was washed with H₂O, brine, dried over MgSO₄.Solvent was removed and crude compound was purified by chromatography onsilica gel. Elution with hexane:acetone mixture (70:30) gave a whitesolid. MS m/z: 201.9(M+H). Calc'd. for C₇H₈BrNO—200.98.

[0611] Preparation CC: 1-(6-Bromo-pyridin-2-yl)-ethanone

[0612] Oxalyl chloride (2.1 mL, 3.81 mmol) in dry CH₂Cl₂ was cooled to−70° C. followed by adding DMSO (0.6 mL, 8.39 mmol) dropwise. Afterstirred for 5 min under −60° C., 1-(6-bromo-pyridin-2-yl)-ethanol (770mg, 3.81 mmol) in dry CH₂Cl₂ (10 mL) was added dropwise. After stirredfor 30 min, TEA (2.7 mL, 19.83 mmol) was added and the resulting mixturewas warmed to RT and stirred for 1 h. The reaction mixture was quenchedwith H₂O. The organic layer was washed with H₂O, brine, and dried overMgSO₄. Solvent was removed and the crude compound was purified bychromatography on silica gel. Elution with hexane:acetone mixture(90:10) gave a white solid. MS m/z: 200.3(M+H). Calc'd. forC₇H₈BrNO—198.96.

[0613] Preparation CD: 2-Bromo-6-(1-piperidin-1-yl-ethyl)-pyridine

[0614] To a stirred solution of 1-(6-bromo-pyridin-2-yl)-ethanone (600mg, 3.01 mmol) in dry CH₂Cl₂ (20 mL) was added piperidine (0.5 mL)followed by NaBH(OAc)₃ (1.3 g, 12.06 mmol) and HOAc (0.7 mL, 6.03 mmol).The mixture was heated at 40° C. for 72 h. The reaction was quenchedwith 2M Na₂CO₃ and stirred 1 h. The organic layer was collected, driedover MgSO₄ and concentrated in vacuo. This crude compound was purifiedby chromatography on silica gel. Elution with hexane:acetone mixture(90:10) gave a light yellow solid. MS m/z: 269.2 (M+H). Calc'd. forC₁₂H₁₇BrN₂—268.06.

[0615] Preparation CE: 2-Hydroxymethyl-piperidine-1-carboxylic acidtert-butyl ester

[0616] Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (50 g, 218.1mmol) in dry THF (300 mL) was cooled to −78° C. followed by addingBH₃-THF solution (261.7 mL, 260.0 mmol) dropwise over 1 h. The resultingmixture was warmed to RT and stirred for 48 h. The reaction was quenchedwith HOAc/H₂O (1:1 ratio, 100 mL). The resulting mixture was partitionedbetween EtOAc and sat. NaHCO₃. The organic layer was washed with moresat. NaHCO₃, H₂O, brine, and dried over MgSO₄. Concentration in vacuogave a white solid. MS m/z: 216.2 (M+H). Calc'd. for C₁₁H₂₁NO₃—215.15.

[0617] Preparation CF: 2-Formyl-piperidine-1-carboxylic acid tert-butylester

[0618] In a manner similar to that described in Preparation CC,2-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg,2.32 mmol) was added to a mixture of oxalyl chloride (1.3 mL, 2.55 mmol)and DMSO (0.36 mL, 5.11 mmol) followed by adding TEA (1.7 mL, 12.07mmol) to give a white solid. MS m/z: 214.2 (M+H). Calc'd. forC₁₁H₁₉NO₃—213.14.

[0619] Preparation CG:2-[(6-Amino-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert-butyl ester

[0620] In a manner similar to that described in Preparation CD,2-formyl-piperidine-1-carboxylic acid tert-butyl ester (360 mg, 1.69mmol) was treated with 2,6-diaminopyridine (184 mg, 1.69 mmol) andstirred at RT to give a light brown oil. MS m/z: 307.3(M+H). Calc'd. forC₁₆H₂₆N4O₂—306.21.

[0621] Preparation CH: 5-Cyano-indole-1-carboxylic acid tert-butyl ester

[0622] To a solution of 5-cyanoindole (9.76 g, 68.7 mmol), 100 mL ofanhydrous CH₃CN, and DMAP (423 mg, 3.5 mmol) was added di-tert-butyldicarbonate (15.78 g, 72.3 mmol). The resulting solution was stirred for18 h then concentrated in vacuo. The resulting solid was redissolved inEtOAc (350 mL) and washed with 1N HCl (aq) (2×25 mL). The acidic aqueoussolution was extracted with EtOAc (2×). The combined EtOAc layers werewashed with brine, dried over MgSO₄, and concentrated in vacuo to give alight yellow solid. MS m/z: 243 (M+1). Calc'd for C₁₄H₁₄N₂O₂—242.47.

[0623] Preparation CI: 5-Thiocarbamoyl-indole-1-carboxylic acidtert-butyl ester

[0624] H₂S (g) was bubbled through a solution of5-cyano-indole-1-carboxylic acid tert-butyl ester (15.71 g, 64.8 mmol),120 mL of pyridine, and TEA (27.5 mL, 197.3 mmol). The reaction wasfollowed by LC-MS and concentrated in vacuo upon completion to give ablack solid. MS m/z: 277 (M+1). Calc'd for C₁₄H₁₆N₂O₂S—276.36.

[0625] Preparation CJ:5-(4-Ethoxycarbonyl-thiazol-2-yl)-indole-1-carboxylic acid tert-butylester

[0626] To a solution of 5-thiocarbamoyl-indole-1-carboxylic acidtert-butyl ester (13.16 g, 47.6 mmol) and 250 mL of EtOH was added ethylbromopyruvate (6.05 mL, 48.2 mmol). The resulting solution was stirredat 60° C. for 1.5 h, then concentrated in vacuo. The resulting solid waspurified by flash chromatography on silica gel using 5% EtOAc/hexane→80%EtOAc/hexane→CH₂Cl₂ as the eluant to give a white solid. MS m/z: 373(M+1). Calc'd for C₁₉H₂₀N₂O₄S—372.44.

[0627] Preparation CK: 5-(4-Carboxy-thiazol-2-yl)-indole-1-carboxylicacid tert-butyl ester

[0628] To a solution of5-(4-ethoxycarbonyl-thiazol-2-yl)-indole-1-carboxylic acid tert-butylester (3.34 g, 9.0 mmol) and 125 mL of THF was added 1N NaOH (aq) (30.0mL, 30.0 mmol). The solution was stirred for 24 h then concentrated invacuo. The crude solid was redissolved in H₂O and acidified with 5%KHSO₄. The solid was filtered and dried in vacuo at 60° C. to give apinkish-white solid. MS m/z: 345 (M+1). Calc'd for C₁₇H₁₆N₂O₄S—344.39.

[0629] Preparation CL: 2-Bromo-thiazole-4-carboxylic acid ethyl ester

[0630] To a stirred mixture of 2-amino-thiazole-4-carboxylic acid ethylester hydrobromide (10 g, 58 mmol), CuSO₄ (26.9 g, 168 mmol) and NaBr(22.7 g, 221 mmol) in 9M H₄SO₄ (aq) (120 mL) at −5° C. −0° C., apre-cooled solution of NaNO₂ (4.4 g, 64 mmol) in H₂O (40 mL) was addedat such a rate to maintain the temperature at or below 0° C. Aftercomplete addition the mixture was maintained at 0° C. for another 30 minthen warmed to RT over 2.5 h. The reaction mixture was diluted with H₂O(120 mL) and extracted with Et₂O (3×100 mL). The aqueous layer wasseparated, basified to pH 12 with 5N NaOH (aq), then extracted with Et₂O(2×100 mL). The organic layers were combined, dried over Na₂SO₄,filtered and the solvent evaporated in vacuo. The residue was purifiedby flash chromatography on silica gel (1:9, EtOAc:hexane) to yield thetitle compound as a white amorphous solid. MS m/z: 235.8, 237.8 (M+H).Calc'd. for C₆H₆BrNO₂S—234.93.

[0631] Preparation CM: 2-Chloro-thiazole-4-carboxylic acid ethyl ester

[0632] 2-Amino-thiazole-4-carboxylic acid ethyl ester hydrobromide(34.46 g, 0.137 mol) was basified with a saturated solution of NaHCO₃(aq) (300 mL) and extracted with EtOAc (8×300mL). The combined organiclayers were dried over Na₂SO₄, filtered and the solvent evaporated invacuo to liberate the free base. To a well stirred suspension of thefree base in 9M H₂SO₄ (aq) (500 mL) at 0° C. to −5° C., CuSO₄ (63.34 g,0.397 mol) and NaCl (30.39 g, 0.520 mol) were added, followed by thedropwise addition of a solution of NaNO₂ (10.39 g, 0.151 mol) in H₂O(150 mL), over 45 min. The mixture was maintained at 0° C. for 1 h thenwarmed to RT. After 1 h at RT the reaction mixture was diluted with H₂O(2 L) and extracted with Et₂O (3×300 mL). The combined organic layerswere dried over Na₂SO₄, filtered and the solvent was evaporated in vacuoto yield the title compound as a pale yellow amorphous solid(sufficiently pure to be used directly in the next step). MS m/z: 192.0(M+H). Calc'd. for C₆H₆ClNO₂S—191.64.

[0633] Preparation CN: 2-Chloro-thiazole-4-carboxylic acid

[0634] To a stirred solution of 2-chlorothiazole-4-carboxylic acid ethylester (20.49 g, 0.107 mol) in THF (180 mL) at RT, a 1M solution of LiOH(aq) (160 mL, 0.160 mol) was added. The resulting solution was heated to65° C. for 1 h. The solvent was evaporated in vacuo. The residue wastreated with brine (100 mL) and acidified to pH 1 with 1M HCl (aq). Theprecipitate was filtered off, washed with H₂O (2×50 mL) and Et₂O (2×50mL) and dried in a vacuum oven at 60° C. for 62 h to yield the titlecompound as a pale yellow solid. MS m/z: 164.1 (M+H). Calc'd. forC₄H₂ClNO₂S—163.58.

[0635] Preparation CO: 2-Chloro-thiazole-4-carbonyl azide

[0636] To a stirred solution of 2-chlorothiazole-4-carboxylic acid(15.30 g, 94 mmol) in anhydrous THF (200 mL) at 0° C., under nitrogen,TEA (26.1 mL, 187 mmol) was added. After 30 min ethyl chloroformate(9.39 mL, 98 mmol) was added dropwise over 10 min. After 25 min asolution of NaN₃ (6.38 g, 98 mmol) in H₂O (110 mL) was added. Themixture was warmed to RT over 1 h then diluted with H₂O (500 mL). Theprecipitate was filtered off and air dried to yield the title compoundas a white amorphous solid. MS m/z: 189.3 (M+H). Calc'd. forC₄HClN₄OS—188.60.

[0637] Preparation CP: 2-Bromo-thiazole-4-carbonyl azide

[0638] To a stirred solution of 2-bromo-thiazole-4-carboxylic acid (5.33g, 25.7 mmol) in anhydrous THF (40 mL) at 0° C., under N₂, TEA (7.18 mL,51.5 mmol) was added. After 30 min ethyl chloroformate (2.59 mL, 27.0mmol) was added dropwise over 10 min. After 25 min a solution of NaN₃(1.76 g, 27.0 mmol) in H₂O (12 mL) was added. The mixture was warmed toRT over 1 h then diluted with H₂O (100 mL). The precipitate was filteredoff and air dried to yield the title compound as a white amorphoussolid. MS m/z: 233.2, 235.2 (M+H). Calc'd. for C₄HBrN₄OS—233.05.

[0639] Preparation CQ:3-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester

[0640] To a stirred solution of 3-(aminomethyl)-1-N-Boc-piperidine (1.64g, 7.65 mmol) and TEA (1.6 mL, 11 mmol) in THF (5 mL) at 0° C., benzylchloroformate (1.15 mL, 8.04 mmol) was added dropwise. The reaction wasmaintained at 0° C. for 1 h, then warmed to RT overnight. The solventwas evaporated in vacuo. The residue was taken up in a saturatedsolution of NH₄Cl (aq) (15 mL) and extracted with EtOAc (10 mL). Theorganic layer was separated, dried over MgSO₄, filtered and the solventwas evaporated in vacuo. The residue was purified by flashchromatography on silica gel (1:4, EtOAc:hexane) to yield the titlecompound as a colorless oil. MS m/z: 349.3 (M+H). Calc'd. forC₁₉H₂₈N₂O₄—348.44.

[0641] Preparation CR: Piperidin-3-ylmethyl-carbamic acid benzyl ester

[0642] To a stirred solution of3-(benxyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester (983 mg, 2.82 mmol) in anhydrous CH₂Cl₂ (10 mL) at RT,under N₂, TFA (3 mL) was added. After 2.5 h the solvent was evaporatedin vacuo and the residue was dissolved in EtOAc (20 mL). The organiclayer was washed with a saturated solution of NaHCO₃ (aq) (30 mL),separated, dried over Na₂SO₄, filtered and the solvent evaporated invacuo to yield the title compound as a pale yellow oil. MS m/z: 249.0(M+H). Calc'd. for C₁₉H₂₈N₂O₄—248.32.

[0643] Preparation CS:2-[3-(Benzyloxycarbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylicacid ethyl ester

[0644] To a stirred solution of piperidin-3-ylmethyl-carbamic acidbenzyl ester (43 mg, 0.17 mmol) in CH₃CN (5 mL), at RT under N₂, K₂CO₃(26 mg, 0.19 mmol) and 2-bromo-thiazole-4-carboxylic acid ethyl ester(41 mg, 0.17 mmol) were added. The resulting mixture was heated atreflux for 29 h. The solvent was evaporated in vacuo. The residue wastreated with a saturated solution of NH₄Cl (aq) (10 mL) and extractedwith EtOAc (10 mL). The organic layer was separated, dried over Na₂SO₄,filtered and the solvent evaporated in vacuo. The residue was purifiedby flash chromatography on silica gel (1:2, EtOAc:hexane) to yield thetitle compound as a colorless oil. MS m/z: 404.2 (M+H). Calc'd. forC₂₀H₂₅N₃O₄S—403.50.

[0645] Preparation CT:2-[3-(Benzyloxycarbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylicacid

[0646] To a stirred solution of2-[3-(benzyloxycarbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylicacid ethyl ester (439 mg, 1.15 mmol) in THF (5 mL) at RT, a 1M solutionof LiOH (aq) (1.72 mL, 1.72 mmol) was added. After 16 h the solvent wasevaporated in vacuo. The residue was treated with brine (25 mL) andacidified to pH 1 with 2N HCl (aq) then extracted with EtOAc (30 mL).The organic layer was separated, dried over Na₂SO₄, filtered and thesolvent evaporated in vacuo to yield the title compound as a colorlessoil. MS m/z: 355.9 (M+H). Calc'd. for C₁₆H₂₅N₃O₄S—355.45.

[0647] Preparation CU: Cyclopropanecarbothioamide

[0648] To a solution of cyclopropanecarboxamide (0.525 g, 6.169 mmol)and Na₂CO₃ (0.654 g, 6.169 mmol) in THF (100 mL) was added solid P₂S₅(2.742 g, 6.169 mmol). The reaction was brought to reflux and kept atthis temperature for 2 h. The reaction mixture was cooled to RT,filtered through Celite® and concentrated in vacuo to yield crudecyclopropane-carbothioamide (used for the next step withoutpurification). MS m/z: 102.1 (M+H) Calc'd. for C₄H₈NS—102.0.

[0649] Preparation CV: Ethyl 2-cyclopropyl-thiazole-4-carboxylate

[0650] To a solution of cyclopropanecarbothiotic acid amide (1.18 g,0.012 mol) in EtOH (60 mL) was added ethylbromopyruvate (1.71 mL, 0.012mol) at RT and the mixture was brought to reflux and kept at thistemperature for 3 h. The reaction mixture was cooled to RT andevaporated to dryness. Crude compound was dissolved in cold CH₃CN (5 mL)and filtered. The filtrate was concentrated in vacuo and the resultingresidue was purified by column chromatography eluting with hexanes:EtOAc(4:1) to give ethyl 2-cyclopropyl-thiazole-4-carboxylate. MS m/z: 197.9(M+H) Calc'd. for C₉H₁₂NO₂S—198.0.

[0651] Preparation CW: 2-Cyclopropyl-thiazole-4-carboxylic acid

[0652] To a mixture of ethyl 2-cyclopropyl-thiazole-4-carboxylate (0.443g, 2.249 mmol) and LiOH monohydrate (0.472 g, 11.243 mmol) was added amixture of THF/MeOH/H₂O (3:1:1, 50 mL). The reaction was stirred at RTfor 24 h. The solution was acidified by addition of conc. HCl (0.1 mL)and the volatiles were removed. Remaining aqueous solution was extractedwith EtOAc (3×20 mL). The combined organic layers were dried over Na₂SO₄and evaporated to dryness. MS m/z: 169.9 (M+H) Calc'd. forC₇H₇NO₂S—170.0.

[0653] Preparation CX: 2-Cyclopropyl-thiazole-4-carbonyl azide

[0654] To a solution of 2-cyclopropyl-thiazole-4-carboxylic acid (0.360g, 2.130 mmol) and TEA (0.59 mL, 4.260 mmol) in THF (10 mL) at 0° C.,was added ethylchloroformate (0.22 mL, 2.343 mmol) and the mixture wasstirred for 30 min. A solution of NaN₃ (0.152 g, 2.343 mmol) in H₂O (10mL) was added to this mixture and warmed to RT. After 1 h, the reactionmixture was diluted with H₂O (10 mL) and extracted with EtOAc (3×20 mL).The combined organic extracts were dried over Na₂SO₄ and evaporated todryness. MS m/z: 195.0 (M+H) Calc'd. for C₇H₇N₄OS—195.0.

[0655] Preparation CY: 2-tert-Butyl-thiazole-4-carbonylazide

[0656] Synthesized from 2,2-dimethylpropionamide following preparationsCU—CX. MS m/z: 211.3 (M+H) Calc'd. for C₈H₁₁N₄OS—211.0.

[0657] Preparation CZ: 3-Sulfamoylthiobenzamide

[0658] 3-Cyanobenzenesulfonamide (12.6 g, 0.067 mol) was added to asolution of TEA (0.8 mL), dry pyridine (0.5 mL) and benzene (30 mL) atRT and cooled to 0° C. H₂S was bubbled through the solution for 20 min.The reaction was stirred at RT for 20 h. The resulting solid wasdissolved in MeOH (30 mL) and transferred for the next step. LC-MS m/z:217 (M+H).

[0659] Preparation DA: 2-(3-Sulfamoyl-phenyl)-thiazole-4-carbonylazide

[0660] Synthesized from 3-sulfamoylthiobenzamide following preparationsCV—CX. MS m/z: 310.2 (M+H). Calc'd. for C₁₀H₈N₅O₃S₂—310.0.

[0661] Preparation DB: Ethyl 2-cyclopropylethynyl-thiazole-4-carboxylate

[0662] To a solution of bromothiazole (319.5 mg, 1.353 mmol),Pd(PhCN)₂Cl₂ (155.7 mg, 0.406 mmol), CuI₂ (51.5 mg, 0.271 mmol) andtri-t-butylphosphine (0.2 M in toluene, 4.4 mL, 0.880 mmol) in dioxane(10 mL) was added DEA (0.21 mL, 2.030 mmol) and ethynylcyclopropane(107.2 mg, 1.624 mmol). The reaction mixture was stirred at RT for 12 h.Volatiles were removed in vacuo and was passed through a pad SiO₂(elution with EtOAc). Chromatography (Hexanes: EtOAc, 9:1) gave pureethyl 2-cyclopropylethynyl-thiazole-4-carboxylate. MS m/z: 222.2 (M+H)Calc'd. for C₁₁H₁₂NO₂S—222.0.

[0663] Preparation DC: 2-Cyclopropylethynyl-thiazole-4-carbonyl azide

[0664] Prepared from ethyl 2-cyclopropylethynyl-thiazole-4-carboxylatefollowing preparations CW—CX. MS m/z: 219.3 (M+H) Calc'd. forC₉H₇N₄OS—219.0.

[0665] Preparation DD: (6-Bromo-pyridin-2-ylmethyl)-isopropyl-amine

[0666] To a stirred solution of 6-bromo-pyridine-2carbaldehyde (1.06 g,5.73 mmol) in dry CH₂Cl₂ (30 mL) was added isopropylamine (0.51 mL, 6.02mmol). The mixture was stirred at RT and under N₂ for 30 min followed bythe addition of NaBH(OAc)₃ (2.42 g, 11.46 mmol) and HOAc (1.3 mL, 22.92mmol). The resulting cloudy light-yellow solution was stirred at RT andunder N₂ for 15 h. A 10% solution of Na₂CO₃ (50 mL) was added to themixture and stirred for 30 min. The organic phase was separated, washedwith H₂O, brine, dried over MgSO₄ and concentrated to afford a lightyellow-oil without further purification. MS m/z: 229.1 (M+H). Calc'd forC₉H₁₃BrN₂: 228.03.

[0667] Preparation DE: (6-Bromo-pyridin-2-ylmethyl)-isopropyl-carbamicacid tert-butyl ester

[0668] To a stirred solution of(6-bromo-pyridin-2-ylmethyl)-isopropyl-amine in CH₂Cl₂ (100 mL) wasadded (Boc)₂O (10.2 g, 46.7 mmol). The resulting mixture was stirred atRT for 3 days. The mixture was concentrated and purified bychromatography on silica gel using 6:1 Hex/EtOAc as eluent to afford avery pale yellow-oil which solidified once cooled to RT. MS m/z: 329.3(M+H). Calc'd for C₁₄H₂₁BrN₂O₂: 328.08.

[0669] Preparation DF: 4-pyrrolidin-1-ylmethylphenol

[0670] To a stirred solution of 4-hydroxylbenzaldehyde (10 g, 81.9 mmol)in anhydrous CH₂Cl₂ (500 mL) at RT, under N₂, pyrrolidine (10.2 mL,122.9 mmol) was added, followed by NaBH(OAc)₃ (34.6 g, 163.9 mmol) andAcOH (19.7 g, 327.8 mmol). After the mixture was stirred at RT for 24 h,a saturated solution of NaHCO₃(aq) (150 mL) was added. The mixture wasvigorously stirred for an additional 1 h and then extracted with CH₂Cl₂(3×200 mL). The combined organic layer was washed with brine (300 mL),dried over MgSO₄, filtered and concentrated under reduced pressure toyield the title compound as amber oil. This was used crude in the nextstep. MS m/z: 178 (M+1). Calc'd for C₁₁H₁₅NO—177.2.

[0671] Preparation DG:2-Bromo-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine

[0672] To a stirred suspension of NaH (2.6 g, 108.5 mmol) in DMF (300mL) at 0° C., under N₂, a solution of 4-pyrrolidin-1-ylmethylphenol (16g, 90.4 mmol) was added slowly. After stirring at 0° C. for 30 min,2,6-dibromopyridine (23.6 g, 99.4 mmol) was added and the resultingmixture was heated at 95° C. for 20 h. After cooling to RT, 200 mL ofH₂O was added and the mixture was extracted with EtOAc (3×300 mL). Thecombined organic layer was washed with brine (3×400 mL), dried overMgSO₄, filtered and concentrated under reduced pressure to yield thetitle compound as an amber solid. This was used crude in the next step.MS m/z: 333 (M+1). Calc'd for C₁₆H₁₇BrN₂O—333.2

[0673] Preparation DH:2-Amino-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine

[0674] A mixture of 2-bromo-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine(20 g) and Cu powder (1 g) in concentrated NH₄OH (250 mL, aq) and IpOH(60 mL) was heated at 100° C. in a sealed flask for 48 h. After coolingto RT, brine (300 mL) was added and the mixture was extracted with EtOAc(3×200 mL). The combined organic layer was washed with brine (300 mL),dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidues were filtered through silica gel pad eluting with MeOH/CH₂Cl₂(5%). The filtrate was concentrated to dryness, then 50 mL of MeOH wasadded. After stirring for a while the solid was filtered to give thetitle compound. MS m/z: 270 (M+1). Calc'd for C₁₆H₁₉N₃O—269.3.

[0675] Preparation DI: 5-tert-Butyl-oxazole-2-carboxylic acid ethylester

[0676] The mixture of N-(3,3-dimethyl-2-oxo-butyl)-oxalamic acid ethylester (0.79 g, 3.67 mmol) and phosphorus oxychloride (2.0 mL, 22.0 mmol)was stirred at 105° C. under N₂ for 2 h, cooled to RT, quenched slowlywith ice-water, extracted with EtOAc. The combined organic portions werewashed with brine, dried with Na₂SO₄, removal of the solvents gave adark brownish oil which was purified by flash column chromatography toyield the title compound. MS m/z: 197.9 (M+H). Calc'd forC₁₀H₁₅NO₃—197.23

[0677] Preparation DJ: 5-tert-Butyl-oxazole-2-carboxylic acid amide

[0678] The mixture of 5-tert-butyl-oxazole-2-carboxylic acid ethylester(0.52 g, 2.64 mmol) and NH₃ (2.0M solution in MeOH, 6.6 mL, 13.2mmol) was stirred at RT under N₂ for 20 h. The solvents were removedunder reduced pressure and the residue was dissolved in EtOAc washedwith brine, dried with Na₂SO₄ and filtered. Removal of the solventsafforded the title compound as a white solid. MS m/z: 169.2 (M+H).Calc'd for C₈H₁₂N₂O₂—168.19.

[0679] Preparation DX: 5-tert-Butyl-oxazole-2-carbothioic acid amide

[0680] In a manner similar to that described in preparation BB, thetitle compound was isolated as a yellow solid. MS m/z: 185.3 (M+H).Calc'd for C₈H₁₂N₂OS—184.26

[0681] Preparation DL:2-(5-tert-Butyl-oxazol-2-yl)-thiazole-4-carboxylic acid ethyl ester

[0682] In a manner similar to that described in preparation BC, thetitle compound was isolated as a white solid. MS m/z: 281.2 (M+H).Calc'd for C₁₃H₁₆N₂O₃S—280.34.

[0683] Preparation DM:2-(5-tert-Butyl-oxazol-2-yl)-thiazole-4-carboxylic acid

[0684] In a manner similar to that described in preparation BD, thetitle compound was isolated as a white solid. MS m/z: 253.3 (M+H).Calcld for C₁₁H₁₂N₂O₃S—252.29.

[0685] Preparation DN: 2-(5-tert-Butyl-oxazol-2-yl)-thiazole-4-carbonylazide

[0686] In a manner similar to that described in preparation BE, thetitle compound was isolated as an off-white solid. MS m/z: 278.2 (M+H)+.Calc'd for C₁₁H₁₁N₅O₂S—277.30.

[0687] Preparation DO: 2-Thiophen-2-yl-thiazole-4-carboxylic acid ethylester

[0688] The mixture of 2-bromo-thiazole-4-carboxylic acid ethyl ester(0.965 g, 4.09 mmol), 2-thiopheneboronic acid (0.52 g, 4.09 mmol),Pd(PPh₃)₄ (0.24 g, 0.20 mmol) in 6.2 mL of 2M Na₂CO₃ (aq) and 25 mL ofethylene glycol dimethyl ether was heated at reflux for 16 h, cooled toRT, diluted with H₂O (25 mL), and extracted with EtOAc (30 mL×3). Thecombined organic portions were washed with brine, dried with Na₂SO₄, andfiltered. Removal of the solvents afforded a light yellowish oil whichwas purified by flash column chromatography (5% to 10% of EtOAc inhexanes). The desired compound was obtained as a pale solid. MS m/z:239.9 (M+H). Calc'd for C₁₀H₉NO₂S₂—239.32.

[0689] Preparation DP:2-(Thiophene-2-sulfonylmethyl)-thiazole-4-carboxylic acid ethyl ester

[0690] In a manner similar to that described in preparation BC, thetitle compound was isolated as a light yellowish viscous oil. MS m/z:318.1 (M+H) Calc'd for C₁₁H₁₁NO₄S₃—317.41.

[0691] Preparation DQ:2-(Thiophene-2-sulfonylmethyl)-thiazole-4-carboxylic acid

[0692] In a manner similar to that described in preparation BD, thetitle compound was isolated as a white solid. MS m/z: 290.0 (M+H).Calc'd for C₉H₇NO₄S₃—289.35.

[0693] Preparation DR:2-(Thiophene-2-sulfonylmethyl)-thiazole-4-carbonyl azide

[0694] In a manner similar to that described in preparation BE, thetitle compound was isolated as a tan solid. MS m/z: 315.1 (M+H). Calc'dfor C₉H₆N₄O₃S₃—314.37.

[0695] Preparation DS: 6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-ylamine

[0696] In a manner similar to that described in Preparation EM, thetitle compound was isolated as a white solid. MS m/z: 208.1 (M+H).Calc'd for C₁₁H₁₇N₃O—207.27.

[0697] Preparation DT:4-(6-Amino-pyridin-2-yloxymethyl)-piperidine-1-carboxylic acidtert-butyl ester

[0698] In a manner similar to that described in Preparation EM, thetitle compound was isolated as a white solid. MS m/z: 308.2 (M+H).Calc'd for C₁₆H₂₅N₃O₃—307.39.

[0699] Preparation DU: D-2-Hydroxymethyl-pyrrolidine-1-carboxylic acidtert-butyl ester

[0700] To a solution of D-prolinol (8 g, 79.2 mmol) and CH₂Cl₂ (150 mL)was added (Boc)₂O (19 g, 87.1 mmol) and 150 mL of sat'd NaHCO₃. Thereaction was stirred at RT for 15 h. Extraction with CH₂Cl₂, washingwith brine, drying (MgSO₄) and concentration in vacuo gaveD-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester as awhite solid. MS m/z: 202.3 (M+H). Calc'd for C₁₀H₁₉NO₃—201.26.

[0701] Preparation DV:2-(6-Bromo-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester

[0702] To a solution of D-2-hydroxymethyl-pyrrolidine-1-carboxylic acidtert-butyl ester (15.9 g, 79.1 mmol) and dry DMF (250 mL) was added NaH(3.8 g, 94.9 mmol, 60% in mineral oil). Stirred at RT for 15 h, thenadded 2,6-dibromopyridine. Heated to 90° C. for 2 h. Cooled andextracted with EtOAc. Washed organic layer with H₂O and brine, dried(MgSO₄) and concentrated in vacuo to give an orange oil. Purified bysilica flash chromatography (10% EtOAc/hexane) to give the desiredcompound as a clear-colorless oil. MS m/z: 358.2 (M+H). Calc'd forC₁₅H₂₁BrN₂O₃—357.24.

[0703] Preparation DW:2-(6-Amino-pyridin-2-yloxymethyl)-pyrrolidin-1-carboxylic acidtert-butyl ester

[0704] In a manner similar to Preparation BW to give2-(6-amino-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester as a viscous green oil. MS m/z: 294.3 (M+H). Calc'd forC₁₅H₂₃N₃O₃—293.36.

[0705] Preparation DX: 2-Bromo-6-(tetrahydro-furan-3-yloxy)-pyridine

[0706] To a solution of (S)-(+)-3-hydroxy-tetrahydrofuran (0.34 mL, 4.2mmol) and dry THF (20 mL) was added NaH (0.17 g, 4.2 mmol, 60%) under N₂at RT. After 5 min, added 2,6-dibromopyridine. Stirred at RT for 4 h.Quenched with H₂O and extracted with EtOAc. Washed organic layer withsaturated NH₄Cl, brine, dried (MgSO₄) and concentrated in vacuo to give2-bromo-6-(tetrahydro-furan-3-yloxy)-pyridine as a clear, colorless oil.MS m/z: 245.2 (M+H). Calc'd for C₉H₁₀BrNO₂—244.09.

[0707] Preparation DY: 2-Bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine

[0708] In a manner similar to preparation DX from tetra-hydro-furfurylalcohol to give 2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine as awhite solid. MS m/z: 259.2 (M+H). Calc'd for C₁₀H₁₂BrNO₂ 258.11.

[0709] Preparation DZ: 2-Bromo-6-(tetrahdyro-furan-2-ylmethoxy)-pyridine

[0710] In a manner similar to preparation DX from tetrahydro-3-furanmethanol to give 2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine as awhite solid. MS m/z: 259.2 (M+H). Calc'd for C₁₀H₁₂BrNO₂ 258.11

[0711] Preparation EA: 6-(Tetrahydro-furan-3-yloxy) -pyridin-2-ylamine

[0712] In a manner similar to preparation BW and2-bromo-6-(tetrahydrofuran-3-yloxy)-pyridine to give6-(tetrahydro-furan-3-yloxy)-pyridin-2-ylamine as a dark-green oil. MSm/z: 181.0 (M+H). Calc'd for C₉H₁₂N₂O₂—180.20.

[0713] Preparation EB:6-(Tetrahydro-furan-2-ylmethoxy)-pyridin-2-ylamine

[0714] In a manner similar to preparation BW from2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine to give6-(tetrahydro-furan-3-yloxy)-pyridin-2-ylamine as a dark-green oil. MSm/z: 384.3 (M+H). Calc'd for C₁₀H₁₄N₂O₂ 194.23.

[0715] Preparation EC:6-(Tetrahydro-furan-3-ylmethoxy)-pyridin-2-ylamine

[0716] In a manner similar to preparation BW from2-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine to give6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-ylamine as a yellow oil. MSm/z: 195.0 (M+H). Calc'd for C₁₀H₁₄N₂O₂ 194.23.

[0717] Preparation ED:6-Bromo-1′-methyl-2′,3′,5′,6′-tetrahydro1′H-[2,4′]bipyridinyl-4′-ol

[0718] To a solution of 1.07 M n-BuLi (36.4 mL) and dry THF (200 mL)chilled to −70° C. under a blanket of N₂ was added 2,6-dibromopyridine(10 g, 38.9 mmol)in 50 mL of dry THF slowly to maintain a temperatureless than −69° C. Stirred at −70° C. for 20 min. Added4-methylpiperidone (4.8 mL, 38.9 mmol) and stirred the mixture at −70°C. for 1 h. Quenched with saturated NaHCO₃ and extracted with EtOAc.Washed the organic layer with brine, dried (MgSO₄) and concentrated invacuo to give6-bromo-1′-methyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol asa light-yellow solid. MS m/z: 272.3 (M+H). Calc'd forC₁₁H₁₅BrN₂O—271.15.

[0719] Preparation EE:6-Bromo-1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl

[0720] To a 150 mL flask containing6-bromo-1′-methyl-2′,3′,5′,6′-tetrahydro-1′H-[2,4′]bipyridinyl-4′-ol (5g, 18.5 mmol) was added conc. H₂SO₄ (50 mL). Heated to 100° C. for 18 h.Cooled and poured onto ice carefully. Neutralized with 5 N NaOH andextracted with EtOAc. Washed with brine, dried (MgSO₄) and concentratedin vacuo. Diluted residue with EtOAc and filtered. Concentrated filtratein vacuo to give6-bromo-1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl as an orangeoil. MS m/z: 254.2 (M+H). Calc'd for C₁₁H₁₃BrN₂ 253.14.

[0721] Preparation EF:1′-Methyl-1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6-ylamine

[0722] In a manner similar to preparation xxx from6-bromo-1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl to give1′-methyl-1′,2,3′,6′-tetrahdyro-(2,4′]bipyridinyl-6-ylamine as a yellowoil. MS m/z: 190.0 (M+H). Calc'd for C₁₁H₁₅N₃ 189.26.

[0723] Preparation EG:1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-ylamine

[0724] A solution of1′-methyl-1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6-ylamine (1.1 g, 5.8mmol) and EtOH (30 mL) was hydrogenated over 20% Pd(OH)₂/C (0.3 g)at 40psi and RT. After 16 h, the mixture was filtered through Celite® andconcentrated in vacuo to give the desired compound as a yellow solid. MSm/z: 192.1 (M+H). Calc'd for C₁₁H₁₇N₃—191.27.

[0725] Preparation EH:6-Bromo-4-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1 -carboxylicacid tert-butyl ester

[0726] In a manner similar to Preparation ED from N-Boc-piperidone togive the desired compound as a yellow oil. MS m/z: 358.0 (M+H). Calc'dfor C₁₅H₂₁BrN₂O₃ 357.24.

[0727] Preparation EI: 6-Bromo-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl

[0728] In a manner similar to Preparation EE from6-bromo-4-hydroxy-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester to give the desired compound as a yellow solid. MSm/z: 240.1 (M+H). Calc'd for C₁₀H₁₁BrN₂ 239.11.

[0729] Preparation EJ:6-Bromo-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

[0730] To a solution of 6-bromo-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl(4.3 g, 17.8 mmol)and CH₂Cl₂ (100 mL) was added saturated NaHCO₃ (100mL) and (Boc)₂O (3.8 g, 17.8 mmol). Stirred at RT for 18 h. Washedorganic layer with brine then dried (MgSO₄) and concentrated in vacuo togive the desired compound as a light-yellow oil. MS m/z: 338.9 (M−H).Calc'd for C₁₅H₁₉BrN₂O₂ 339.23.

[0731] Preparation EK:6-Amino-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

[0732] In a manner similar to Preparation EG from6-amino-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester to give the desired compound as a yellow oil. MS m/z:278.3(M+H). Calc'd for C₁₅H₂₃N₃O₂ 277.36.

[0733] Preparation EL:6-Amino-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester

[0734] In a manner similar to Preparation BW from6-bromo-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester to give the desired compound as a yellow oil. MS m/z:275.6 (M+H). Calc'd for C₁₅H₂₁N₃O₂ 275.35.

[0735] Preparation EM: 3-(6-Bromo-pyridin-2-ylamino)-propan-1-ol

[0736] A solution of 2,6-dibromopyridine (10 g, 42 mmol) and3-aminopropanol (3.5 mL, 46 mmol) in THF (60 mL) was stirred at refluxfor 48 h. The reaction mixture was diluted with EtOAc and washed withH₂O and brine, dried (MgSO₄) and concentrated in vacuo to give3-(6-bromo-pyridin-2-ylamino)-propan-1-ol as a light-yellow oil whichcrystallized on standing at RT to a white solid. MS m/z: 232.0 (M+H).Calc'd for C₈H₁₁BrN₂O 231.09.

[0737] Preparation EN:(6-Bromo-pyridin-2-yl)-[3-(tetrahydro-pyran-2-yloxy)-propyl]-amine

[0738] A solution of 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol (4.2 g,18 mmol), 3,4-dihydro-2H-pyran (1.6 mL, 18 mmol), TsOH (0.34 g, 1.8mmol) and CH₂Cl₂ (100 mL) were stirred at RT. After 15 h, the reactionwas quenched with saturated NaHCO₃ and extracted with EtOAc. The organiclayer was washed with brine, dried (MgSO₄) and concentrated in vacuo togive the desired compound as a pale-yellow oil. MS m/z: 316.0 (M+H).Calc'd for C₁₃H₁₉BrN₂O₂ 315.21.

[0739] Preparation EO:N-[3-(Tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diamine

[0740] In a manner similar to Preparation BW from(6-bromo-pyridin-2-yl)-[3-(tetrahydro-pyran-2-yloxy)-propyl]-amine togive the desired compound as green oil. MS m/z: 252.0 (M+H). Calc'd forC₁₃H₂₁N₃O₂ 251.32.

[0741] Preparation EP:1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-[3-(tetrahydro-pyran-2-yloxy)-propylamino]-pyridin-2-yl]-urea

[0742] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide andN-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diamine were heatedtogether in toluene to give the desired compound as a yellow solid. MSm/z: 452.9 (M−H). Calc'd for C₂₂H₂₆N₆O₃S 454.55.

[0743] Preparation EQ:1-(2-Bromo-thiazol-4-yl)-3-{6-[3-(tetrahydro-pyran-2-yloxy)-propylamino]-pyridin-2-yl}-urea

[0744] In a manner similar to Example 234, 2-bromo-thiazole-4-carbonylazide and N-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diaminewere heated together in toluene to give the desired compound as a yellowsolid. MS m/z: 457.3 (M−H). Calc'd for C₁₇H₂₂BrN₅O₃S 456.36.

[0745] Preparation ER: 1-Acetyl-1H-indazole-5-carbonitrile

[0746] In a manner similar to that described by J. Sun, et al, J.O.C.,1997, p. 5627 from 4-amino-3-methylbenzo-nitrile, acetic anhydride, KOAcand CHCl₃ to give 1-acetyl-1H-indazole-5-carbonitrile as a yellow solid.MS m/z: 186.0 (M+H). Calc'd for C₁₀H₇N₃O 185.18.

[0747] Preparation ES: 1-Acetyl-1H-indazole-5-carbothioic acid amide

[0748] To a solution of 1-acetyl-1H-indazole-5-carbonitrile (1.1 g, 6mmol), Et₃N (2.5 mL, 17.8 mmol) and THF (20 mL) was bubbled in H₂S gasover 10 min. Stirred at 0° C. for 24 h. Concentrated in vacuo to give ayellow solid which was triturated with CH₂Cl₂ and filtered insolublesolid to give 1-acetyl-1H-indazole-5-carbothioic acid amide as a yellowsolid. MS m/z: 220.0 (M+H). Calc'd for C₁₀H₉N₃OS 219.26.

[0749] Preparation ET:2-(1-Acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid ethyl ester

[0750] In a manner similar to Preparation CV from1-acetyl-1H-indazole-5-carbothioic acid amide to give2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid ethyl ester as awhite solid. MS m/z: 316.2 (M+H). Calc'd for C₁₅H₁₃N₃O₃S 315.35.

[0751] Preparation EU:2-(1-Acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid

[0752] In a manner similar to Preparation CW from2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid ethyl ester togive 2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid as a yellowsolid following re-protection with Ac₂O, Et₃N, and THF. MS m/z: 286.1(M−H). Calc'd for C₁₃H₉N₃O₃S 287.29.

[0753] Preparation EV: 2-(1-Acetyl-1H-indazol-5-yl)-thiazole-4-carbonylazide

[0754] In a manner similar to Preparation CX from2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carboxylic acid to give2-(1-acetyl-1H-indazol-5-yl)-thiazole-4-carbonyl azide as a white solid.MS m/z: (M+H). Calc'd for C₁₃H₈N₆O₂S 312.31.

[0755] Preparation EW: 6-(1-Piperidin-1-yl-ethyl)-pyridin-2-ylamine

[0756] In a manner similar to that described in Preparation BW,2-bromo-6-(1-piperidin-1-yl-ethyl)-pyridine (370 mg, 1.37 mmol) washeated with NH₄OH (18 mL), IpOH (10 mL), and Cu (30 mg) in sealed tubeto give a brown oil. MS m/z: 206.1 (M+H). Calc'd. for C₁₂H₁₉N₃—205.16.

[0757] Preparation EX: (6-Amino-pyridin-2-ylmethyl)-isopropyl-carbamicacid tert-butyl ester

[0758] Prepared in a manner similar to preparation BW to give a paleyellow solid. EI-MS m/z 266.3 (M+H). Calc'd for C₁₄H₂₃N₃O₂: 265.18.

EXAMPLE 1

[0759]

[0760] N,N′-bis [2-(3-Pyridinyl)-4-thiazolyl]urea

[0761] To a 50 mL round bottomed flask were added 0.106 g (0.458 mmol)of 2-(3-pyridinyl)-4-thiazolyl-carbonylazide, toluene (10 mL) and 5drops of H₂O. The mixture was heated at 95° C. for 4 h then cooled toRT. The precipitate that formed was filtered, washed with a minimumamount of toluene and dried under high vacuum to give the product as apale yellow solid. MS m/z: 381.5 (M+H). Calc'd. for C₁₇H₁₂N₆OS₂—380.453.

EXAMPLE 2

[0762]

[0763] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-pyridinylurea

[0764] To a solution of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (60mg, 0.260 mmol) in 10 mL toluene was added 2-aminopyridine (35 mg, 0.372mmol). The mixture was heated at 95° C. for 18 h then cooled to RT andfiltered. The precipitate was washed with toluene (3 mL) and dried underhigh vacuum to give the product as a pale yellow solid. MS m/z: 298.5(M+H). Calc'd. for C₁₄H₁₁N₅OS—297.341.

EXAMPLE 3

[0765]

[0766] N,N′-bis[2-(4-Pyridinyl)-4-thiazolyl]urea

[0767] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (130 mg, 0.562 mmol) was heatedin toluene (10 mL) containing 4 drops of H₂O to give the product as apale yellow solid. MS m/z: 381.5 (M+H). Calc'd. for C₁₇H₁₂N₆OS₂—380.453.

EXAMPLE 4

[0768]

[0769] N-[2-(3-Pyridinyl)-4-thiazolyl]-N′-2-pyridinylurea

[0770] In a manner similar to that described in Example 2,2-(3-pyridinyl)-4-thiazolylcarbonylazide (48 mg, 0.208 mmol) and2-aminopyridine (24 mg, 0.255 mmol) were heated in toluene (10 mL) togive the product as a pale yellow solid. MS m/z: 298.4 (M+H). Calc'd.for C₁₄H₁₁N₅OS—297.341.

EXAMPLE 5

[0771]

[0772] N-[2-(2-Pyridinyl) -4-thiazolyl]-N′-2-pyridinylurea

[0773] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-aminopyridine (318 mg, 2.6 mmol) were heated in toluene (10 mL) at100° C. for 14 h. After cooling to RT, the solids were collected byfiltration and washed first with toluene (2×20 mL) followed by Et₂O(2×10 mL) and cold EtOAc (3×5 mL). The solid was recrystallized fromEtOAc to afford the product as an off-white solid: m.p. 233-235° C. MSm/z: 298 (M+H). Calc'd for C₁₄H₁₁N₅OS 297.341.

EXAMPLE 6

[0774]

[0775] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-(6-methylpyridinyl)urea

[0776] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (69 mg, 0.298 mmol) and2-amino-6-methylpyridine (101 mg, 0.934 mmol) were heated in toluene (10mL) to give the product as a pale yellow solid. MS m/z: 312.5 (M+H).Calc'd. for C₁₅H₁₃N₅OS—311.368.

EXAMPLE 7

[0777]

[0778] N-[2-(3-Pyridinyl)-4-thiazolyl)-N′-2-(6-methylpyridinyl)urea

[0779] In a manner similar to that described in Example 2,2-(3-pyridinyl)-4-thiazolylcarbonylazide (78 mg, 0.337 mmol) and2-amino-6-methylpyridine (101 mg, 0.934 mmol) were heated in toluene (10mL) to give the product as a pale yellow solid. MS m/z: 312.2 (M+H).Calc'd. for C₁₅H₁₃N₅OS—311.368.

EXAMPLE 8

[0780]

[0781] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-(5-methylpyridinyl)urea

[0782] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (72 mg, 0.311 mmol) and2-amino-5-methylpyridine (106 mg, 0.981 mmol) were heated in toluene (10mL) to give the product as a pale yellow solid. MS m/z: 312.5 (M+H).Calc'd. for C₁₅H₁₃NOS—311.368.

EXAMPLE 9

[0783]

[0784] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-(3-methylpyridinyl)urea

[0785] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (135 mg, 0.584 mmol) and2-amino-3-methylpyridine (200 mg, 1.98 mmol) were heated in toluene (10mL) to give the product as a pale yellow solid. MS m/z: 312.4 (M+H).Calc'd. for C₁₅H₁₃N₅OS 311.368.

EXAMPLE 10

[0786]

[0787] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-pyridinyl-N′-methylurea

[0788] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (71 mg, 0.310 mmol) and2-methylaminopyridine (210 mg, 1.94 mmol) were heated in toluene (7 mL)to give the product as pale yellow crystals. MS m/z: 312.5 (M+H).Calc'd. for C₁₅H₁₃N₅OS—311.368.

EXAMPLE 11

[0789]

[0790] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-(6-ethylpyridinyl)urea

[0791] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (75 mg, 0.324 mmol) and2-amino-6-ethylpyridine (200 mg, 1.63 mmol) were heated in toluene (8mL) to give the product as a pale yellow solid. MS m/z: 326.5 (M+H).Calc'd. for C₁₆H₁₅N₅OS—325.395.

EXAMPLE 12

[0792]

[0793] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-(4-ethylpyridinyl)urea

[0794] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (82 mg, 0.355 mmol) and2-amino-4-ethylpyridine (106 mg, 0.867 mmol) were heated in toluene (10mL) to give the product as a pale yellow solid. MS m/z: 326.5 (M+H).Calc'd. for C₁₆H₁₅N₅OS—325.395.

EXAMPLE 13

[0795]

[0796] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-(6-propylpyridinyl)urea

[0797] In a manner similar to that described in Example 3,2-(4-pyridinyl)-4-thiazolylcarbonylazide (89 mg, 0.385 mmol) and2-amino-6-(n-propyl)pyridine (171 mg, 1.25 mmol) were heated in toluene(10 mL) to give the product as a pale yellow solid. MS m/z: 339.4 (M+H).Calc'd. for C₁₇H₁₇N₅OS—339.422.

EXAMPLE 14

[0798]

[0799]N-[2-(2-Ethyl-4-pyridinyl)-4-thiazolyl]-N′-2-(6-propylpyridinyl)urea

[0800] In a manner similar to that described in Example 6,2-(4-(2-ethyl)-pyridinyl)-4-thiazolylcarbonylazide (460 mg, 1.77 mmol)and 2-amino-6-(n-propyl)pyridine (483 mg, 3.55 mmol) were heated intoluene (20 mL) at 100° C. for 14 h. After cooling to RT, the solidswere collected by filtration and washed first with toluene (2×20 mL)followed by EtOAc:Et₂O (4:1) (4×20 mL) to give the product as anoff-white solid: m.p. 204-206° C. MS m/z: 368 (M+H). Calc'd. forC₁₉H₂₁N₅OS—367.476.

EXAMPLE 15

[0801]

[0802] N-[3-(3-Pyridinyl)phenyl]-N′-2-(6-propylpyridinyl)urea

[0803] To a suspended anhydrous solution of 3-pyridylaniline (90 mg,0.53 mmol) in dry toluene (4 mL) was added phosgene (0.36 mL, 0.69 mmol,20% in toluene) followed by DIEA (0.20 mL, 1.05 mmol) under anatmosphere of argon. After stirring for 0.5 h at RT,2-amino-6-n-propylpyridine (72 mg, 0.53 mmol) in dry toluene (4 mL) wasadded dropwise into the mixture. The resulting mixture was stirred at RTfor 18 h. The organic solvent was removed under vacuum. The residue waspurified by chromatography on flash silica gel using 2% MeOH/CH₂Cl₂ aseluant to obtain the final urea as an off-white solid. MS m/z :333.4(M+H). Calc'd. for C₂₀H₂₀N₄O—332.405.

EXAMPLE 16

[0804]

[0805] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-4-benzimidazolylurea

[0806] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (32 mg, 0.138 mmol) and4-aminobenzimidazole (32 mg, 0.240 mmol) were heated in toluene (8 mL).The crude product was recrystallized with CH₃CN:MeOH (˜10:1) to give theproduct as a pale brown solid. MS m/z: 337.5 (M+H). Calc'd. forC₁₆H₁₂N₆OS—336.378.

EXAMPLE 17

[0807]

[0808] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-3-(1-bromoisoquinolinyl)urea

[0809] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (61 mg, 0.264 mmol) and3-amino-1-bromo-isoquinoline (120 mg, 0.538 mmol) were heated in toluene(10 mL) to give the product as a pale yellow solid. MS m/z: 427.2 (M+H).Calc'd. for C₁₈H₁₂BrN₅OS—426.297.

EXAMPLE 18

[0810]

[0811] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-[4-(3-pyridinyl)-2thiazolyl]urea

[0812] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (36 mg, 0.298 mmol) and2-amino-4-(3-pyridyl)-thiazole (29 mg, 163 mmol) were heated in toluene(10 mL) to give the product as a pale yellow solid. MS m/z: 381.5 (M+H).Calc. for C₁₇H₁₂N₆OS₂—380.453.

EXAMPLE 19

[0813]

[0814] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-quinolinylurea

[0815] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (38 mg, 0.164 mmol) and2-aminoquinoline (53 mg, 0.370 mmol) were heated in toluene (10 mL) togive the product as a pale yellow solid. MS m/z: 348.4 (M+H). Calc. forC₁₈H₁₃N₅OS—347.401.

EXAMPLE 20

[0816]

[0817]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-(5-trifluoromethylpyridinyl)urea

[0818] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (40 mg, 0.173 mmol) and2-amino-5-trifluoromethylpyridine (165 mg, 1.02 mmol) were heated in 10mL toluene to give the product as a pale yellow solid. MS m/z: 366.3(M+H). Calc'd. for C₁₅H₁₀F₃N₅OS—365.339.

EXAMPLE 21

[0819]

[0820] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-thiazolylurea

[0821] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (70 mg, 0.303 mmol) and2-aminothiazole (38 mg, 0.38 mmol) were heated in toluene (12 mL) togive the product as a pale yellow solid. MS m/z: 304.4 (M+H). Calc'd.for C₁₂H₉N₅OS₂—303.366.

EXAMPLE 22

[0822]

[0823]N-[2-(3-Pyridinyl)-4-thiazolyl]-N′-[4-(3-pyridinyl)-2-thiazolyl]urea

[0824] In a manner similar to that described in Example 2,2-(3-pyridinyl)-4-thiazolylcarbonylazide (36 mg, 0.156 mmol) and2-amino-4-(3-pyridinyl)thiazole (30 mg, 0.169 mmol) were heated intoluene (8 mL) to give the product as a pale yellow solid. MS m/z: 381.5(M+H). Calc'd. for C₁₇H₁₂N₆OS₂—380.453.

EXAMPLE 23

[0825]

[0826] N-[2-(3-Pyridinyl)-4-thiazolyl]-N′-2-thiazolylurea

[0827] In a manner similar to that described in Example 2,2-(3-pyridinyl)-4-thiazolylcarbonylazide (59 mg, 0.255 mmol) and2-aminothiazole (27 mg, 268 mmol) were heated in toluene (10 mL) to givethe product as a pale yellow solid. MS m/z: 304.3 (M+H). Calc'd. forC₁₂H₉N₅OS₂—303.366.

EXAMPLE 24

[0828]

[0829] N-[2-(3-Pyridinyl)-4-thiazolyl]-N′-[4-phenyl-2-thiazolyl]urea

[0830] In a manner similar to that described in Example 2,2-(3-pyridinyl)-4-thiazolylcarbonylazide (49 mg, 0.211 mmol) and2-amino-4-phenylthiazole (39 mg, 0.218 mmol) were heated in toluene (10mL) to give the product as a pale yellow solid. MS m/z: 380.5 (M+H).Calc'd. for C₁₈H₁₃N₅OS_(2—)379.465.

EXAMPLE 25

[0831]

[0832]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-diethylamino)pyridinyl]urea

[0833] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (100 mg,0.43 mmol) and 2-amino-6-(N,N-diethylamino)pyridine (150 mg, 0.91 mmol)in toluene (3 mL) was heated at 70° C. for 1 h, and then at 80° C. for 5h. After the mixture was cooled to RT the solvent was removed in vacuoand the crude product was purified by chromatography on silica gel (1:10MeOH(NH₃)/CH₂Cl₂) to giveN-[2-(4-pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-diethylamino)pyridinyl]urea.MS m/z: 369 (M+1). Calc'd. for C₁₈H₂₀N₆OS—368.463.

EXAMPLE 26

[0834]

[0835]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-diethylamino)pyridinyl]ureahydrochloride

[0836]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-diethylamino)pyridinyl]urea(Example 25) was dissolved in 5 ml of MeOH/CH₂Cl₂ (1:1) and (1M) HCl (8mL) in Et₂O solution was added. The solvents were removed in vacuo toafford the title salt as a yellow solid.

EXAMPLE 27

[0837]

[0838]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(4morpholinyl)pyridinyl]urea

[0839] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (100 mg,0.43 mmol) and 2-amino-6-(4-morpholinyl)pyridine (150 mg, 0.84 mmol) intoluene (5 mL) was heated at 80° C. for 5 h. After the mixture wascooled to RT the solvent was removed in vacuo and the crude product waspurified by chromatography on silica gel (1:10 MeOH(NH₃)/CH₂Cl₂) toafford the title compound as a light yellow solid. MS m/z: 383 (M+1).Calc'd. for C₁₈H₁₈N₆O₂S—382.446.

EXAMPLE 28

[0840]

[0841]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(1-piperdinyl)pyridinyl]urea

[0842] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (100 mg,0.43 mmol) and 2-amino-6-(1-piperidinyl)pyridine (100 mg, 0.56 mmol) intoluene (3 mL) was heated at 80° C. for 4 h. After cooling to RT, H₂Owas added and the mixture was extracted with EtOAc (3×80 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bychromatography on silica gel (1:20 MeOH/CH₂Cl₂) to afford the titlecompound as a light yellow solid. MS m/z: 381 (M+1). Calc'd forC₁₉H₂₀N₆OS—380.475.

EXAMPLE 29

[0843]

[0844]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-diethylaminomethylamino)pyridinyl]urea

[0845] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (100 mg,0.43 mmol) and 2-amino-6-(N,N-diethylaminomethyl)pyridine (150 mg, 0.84mmol) in toluene (5 mL) was heated at 80° C. for 5 h. After the mixturewas cooled to RT the solvent was removed in vacuo and the crude productwas purified by chromatography on silica gel (1:10 MeOH(NH₃)/CH₂Cl₂) togive the base. MS m/z: 383 (M+1). Calc'd. for C₁₉H₂₂N₆OS—382.49.

EXAMPLE 30

[0846]

[0847]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-diethylaminomethylamino)pyridinyl]ureahydrochloride

[0848]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-diethylaminomethylamino)pyridinyl]urea(Example 29) was dissolved in 5 ml of MeOH/CH₂Cl₂ (1:1) and 1M HCl (8mL) in Et₂O solution was added. The solvents were removed in vacuo toafford the title salt as a yellow solid.

EXAMPLE 31

[0849]

[0850]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(1-methyl-4-piperazinyl)pyridinyl]urea

[0851] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (100 mg,0.43 mmol) and 2-amino-6-(1-(4-methyl)piperazinyl)pyridine (100 mg, 5.21mmol) in toluene (5 mL) was heated at 80° C. for 5 h. After the mixturewas cooled to RT the solvent was removed in vacuo. The crude product waspurified by chromatography on silica gel (1:10 MeOH(NH₃)/CH₂Cl₂) to giveN-[2-(4-pyridinyl)-4-thiazolyl]-N′-2-[6-(1-methyl-4-piperazinyl)pyridinyl]urea.m.p. 251-253° C. MS m/z: 396 (M+1). Calc'd. for C₁₉H₂₂N₆OS—395.489.

EXAMPLE 32

[0852]

[0853]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(1-methyl-4-piperazinyl)pyridinyl]ureahydrochloride

[0854]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(1-methyl-4-piperazinyl)pyridinyl]urea(Example 31) was dissolved in 5 ml of MeOH/CH₂Cl₂ (1:1) and 1M HCl (8mL) in Et₂O solution was added. The solvents were removed in vacuo toafford the title salt as a yellow solid.

EXAMPLE 33

[0855]

[0856]N-[2-(4-Pyridinyl)-4-thiazolyl-N′-2-[6-[3-(1-morpholinyl)propyl]amino]pyridinyl]urea

[0857] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (200 mg,0.86 mmol) and 2-amino-6-(3-(N-morpholinyl)propylamino)pyridine (300 mg,1.27 mmol) in toluene (8 mL) was heated at 70° C. for 1 h, and then at80° C. for 5 h. After the mixture was cooled to RT the solvent wasremoved in vacuo and the product was purified by chromatography onsilica gel (1:10 MeOH(NH₃)/CH₂Cl₂) to afford the title compound as alight yellow solid: m.p. 215-217° C. MS m/z: 440 (M+1). Calc'd. forC₂₁H₂₅N₇O₂S—439.541.

EXAMPLE 34

[0858]

[0859][[(2-(4-Pyridinyl)-4-thiazolylamino)carbonyl]amino]-2-pyridinyl-5-carboxamide

[0860] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (100 mg,0.43 mmol) and 6-aminonicotinamide (200 mg, 1.45 mmol) in toluene (5 mL)was heated at 80° C. for 6 h. After the mixture was cooled to RT thesolvent was removed in vacuo and the crude product was purified bychromatography on silica gel (1:10 MeOH(NH₃)/CH₂CI₂) to afford the titlecompound as a light yellow solid: m.p. 255-257° C. MS m/z: 341 (M+1).Calc'd for C₁₅H₁₂N₆O₂S—340.37.

EXAMPLE 35

[0861]

[0862]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(N″,N″-aminoethylamino)pyridinyl]urea

[0863] A mixture of 2-(4-pyridinyl)-4-thiazolyl-carbonylazide (200 mg,0.86 mmol) and 2-amino-6-(N,N-dimethylethylenediamino)pyridine (234 mg,1.30 mmol) in toluene (10 mL) was heated at 70° C. for 1 h, and then at80° C. for 5 h. After the mixture was cooled to RT the solvent wasremoved in vacuo and the crude product was purified by chromatography onsilica gel (1:10 MeOH(NH₃)/CH₂Cl₂) to afford the title compound as alight yellow solid: m.p. 210-212° C. MS m/z: 384 (M+1). Calc'd. forC₁₈H₂₁N₇OS—383.48.

EXAMPLE 36

[0864]

[0865] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(3-methylpyridinyl)urea

[0866] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (500 mg, 2.2 mmol) and2-amino-3-methylpyridine (183 mg, 6.6mmol) were heated in toluene (20mL) at 100° C. for 12 h. After cooling to RT, the solids were collectedby filtration and washed first with toluene (2×20 mL) followed by Et₂O(3×10 mL). Recrystallization of the product from MeOH afforded thedesired material: m.p. 235-237° C. MS m/z: 312 (M+H). Calc'd. forC₁₅H₁₃N₅OS—311.368.

EXAMPLE 37

[0867]

[0868]N-[2-(3-Pyridinyl)-4-thiazolyl]-N′-[5-(1,1-dimethylethyl)-3-isoxazolyl]urea

[0869] 2-(3-Pyridinyl)-4-thiazolylcarbonylazide (300 mg, 1.30 mmol) and3-amino-5-(tert-butyl)isoxazole (491 mg, 3.50 mmol) were heated intoluene (10 mL) at 95° C. for 24 h. After cooling to RT, the solids werecollected by filtration and washed first with toluene (2×20 mL) followedby cold EtOAc (3×10 mL) to give the product as an off-white solid: m.p.230-232° C. MS m/z: 344 (M+H). Calc'd. for C₁₆H₁₇N₅O₂S—343.410.

EXAMPLE 38

[0870]

[0871] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(5-methylpyridinyl)urea

[0872] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-amino-5-methylpyridine (183 mg, 1.7 mmol) were heated in toluene (15mL) at 100° C. for 12 h. After cooling to RT, the solids were collectedby filtration and washed first with toluene (2×20 mL) followed byEt₂O:EtOAc (3:1) (3×10 mL) to afford the product as a tan solid: m.p.228-230° C. MS m/z: 312 (M+H). Calc'd. for C₁₅H₁₃N₅OS—311.368.

EXAMPLE 39

[0873]

[0874] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-3-quinolinylurea

[0875] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (53 mg, 0.229 mmol) and3-aminoquinoline (36 mg, 260 mmol) were heated in toluene (10 mL) togive the product as a pale yellow solid. MS m/z: 348.5 (M+H). Calc. forC₁₈H₁₃N₅OS—347.401.

EXAMPLE 40

[0876]

[0877] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(4,6-dimethylpyridinyl)urea

[0878] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-amino-4,6-dimethylpyridine (210 mg, 1.7 mmol) were heated in toluene(15 mL) at 100° C. for 12 h. After cooling to RT, the solids werecollected by filtration and washed first with toluene (2×20 mL) followedby Et₂O:EtOAc (3:1) (3×10 mL) to afford the product as a tan solid: m.p.232-234° C. MS m/z: 326 (M+H). Calc'd. for C₁₆H₁₅N₅OS—325.394.

EXAMPLE 41

[0879]

[0880] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(6-methylbenzthiazolyl)urea

[0881] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-amino-6-methylbenzothiazole (279 mg, 1.7 mmol) were heated in toluene(15 mL) at 100° C. for 12 h. After cooling to RT, the solids werecollected by filtration and washed first with toluene (2×20 mL) followedby Et₂O:EtOAc (3:1) (3×10 mL) to afford the product as a tan solid: m.p.263-265° C. MS m/z: 312 (M+H). Calc'd. for C₁₇H₁₃N₅OS₂—367.456.

EXAMPLE 42

[0882]

[0883] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(4-methylpyridinyl)urea

[0884] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-amino-4-methylpyridine (183 mg, 1.7 mmol) were heated in toluene (15mL) at 100° C. for 12 h. After cooling to RT, the solids were collectedby filtration and washed first with toluene (2×20 mL) followed byEt₂O:EtOAc (3:1) (3×10 mL) to afford the product as an off-white solid:m.p. 217-219° C. MS m/z: 312 (M+H). Calc'd. for C₁₅H₁₃N₅OS—311.368.

EXAMPLE 43

[0885]

[0886] N-[2-(3-Pyridinyl)-4-thiazolyl]-N′-2-(6-ethylpyridinyl)urea

[0887] In a manner similar to that described in Example 2,2-(3-pyridinyl)-4-thiazolylcarbonylazide (186 mg, 0.804 mmol) and2-amino-6-ethylpyridine (364 mg, 2.78 mmol) were heated in toluene (12mL) to give the product as a pale yellow solid. MS m/z: 326.5 (M+H).Calc'd. for C₁₆H₁₅N₅OS—325.395.

EXAMPLE 44

[0888]

[0889] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(6-ethylpyridinyl)urea

[0890] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-amino-6-ethylpyridine (318 mg, 2.6 mmol) were heated in toluene (10mL) at 100° C. for 14 h. After cooling to RT, the solids were collectedby filtration and washed first with toluene (2×20 mL) followed by Et₂O(2×10 mL) and cold EtOAc (3×5 mL) to give the product as a beige solid:m.p. 213-215° C. MS m/z: 326 (M+H). Calc'd. for C₁₆H₁₅N₅OS—325.395.

EXAMPLE 45

[0891]

[0892] N-[2-(4-Methoxyphenyl)-4-thiazolyl]-N′-2-(6-propylpyridinyl)urea

[0893] 2-(4-Methoxyphenyl)-4-thiazolylcarbonylazide (280 mg, 1.1 mmol)and 2-amino-6-n-propylpyridine (439 mg, 3.2 mmol) were heated in toluene(20 mL) at 100° C. for 14 h. After cooling to RT, the solids werecollected by filtration and washed first with toluene (2×20 mL) followedby Et₂O (2×10 L) and cold EtOAc (3×5 mL) to afford the product as anoff-white solid. m.p. 223-225° C. MS m/z: 369 (M+H). Calc'd forC₁₉H₂₀N₄O₂S—368.461.

EXAMPLE 46

[0894]

[0895] N-[2-(4-Hydroxyphenyl)-4-thiazolyl]-N′-2-(6-propylpyridinyl)urea

[0896] To a stirred solution of Example 45 (100 mg, 0.271 mmol) inCH₂Cl₂ (5 mL), boron tribromide was added dropwise at RT. The mixturewas stirred for 8 h before adding H₂O (10 ml) and the resulting solidswere collected by filtration. This material was washed several timeswith H₂O and then EtOAc followed by drying in vacuo to afford thedesired product as a light yellow solid: m.p. 227-229° C. MS m/z: 355(M+H). Calc'd for C₁₈H₁₈N₄O₂S—354.434.

EXAMPLE 47

[0897]

[0898] N-[2-(3-Methoxyphenyl)-4-thiazolyl]-N′-2-(6-propylpyridinyl)urea

[0899] 2-(3-Methoxyphenyl)-4-thiazolylcarbonylazide (1.0 g, 3.8 mmol)and 2-amino-6-n-propylpyridine (1.05 g, 7.7 mmol) were heated in toluene(40 mL) at 100° C. for 12 h. After cooling to RT, the solids werecollected by filtration and washed first with toluene (2×40 mL) followedby cold EtOAc (3×20 mL) to afford the product as a white solid: m.p.192-194° C. MS m/z: 369 (M+H). Calc'd for C₁₉H₂₀N₄O₂S—368.461.

EXAMPLE 48

[0900]

[0901] N-[2-(3-Methoxyphenyl)-4-thiazolyl]-N′-2-pyridinylurea

[0902] 2-(3-Methoxyphenyl)-4-thiazolylcarbonylazide (1.0 g, 3.8 mmol)and 2-aminopyridine (0.72 g, 7.7 mmol) were heated in toluene (40 mL) at100° C. for 12 h. After cooling to RT, the solids were collected byfiltration and washed first with toluene (2×40 mL) followed by coldEtOAc (3×20 mL) to afford the product as a white solid: m.p. 201-203° C.MS m/z: 327 (M+H). Calc'd for C₁₆H₁₄N₄O₂S—326.380.

EXAMPLE 49

[0903]

[0904] N-[2-phenyl-4-thiazolyl]-N′-2-(6-ethylpyridinyl)urea

[0905] In a manner similar to that described in Example 2,2-phenyl-4-thiazolylcarbonylazide (150 mg, 0.652 mmol) and2-amino-6-ethylpyridine (250 mg, 2.05 mmol) were heated in toluene (10mL) to give the product as a pale yellow solid. MS m/z: 325.4 (M+H).Calc'd for C₁₇H₁₆N₄OS—324.407.

EXAMPLE 50

[0906]

[0907] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(4-ethylpyridinyl)urea

[0908] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-amino-4-ethylpyridine (208 mg, 1.7 mmol) were heated in toluene (15mL) at 100° C. for 12 h. After cooling to RT, the solids were collectedby filtration and washed first with toluene (2×20 mL) followed byEt₂O:EtOAc (3:1) (3×10 mL) to afford the product as a tan solid: m.p.196-198° C. MS m/z: 326 (M+H). Calc'd. for C₁₆H₁₅N₅OS—325.395.

EXAMPLE 51

[0909]

[0910] N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-(6-propylpyridinyl)urea

[0911] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (200 mg, 0.87 mmol) and2-amino-6-(n-propyl)pyridine (350 mg, 2.6 mmol) were heated in toluene(10 mL) at 100° C. for 14 h. After cooling to RT, the solids werecollected by filtration and washed first with toluene (2×20 mL) followedby Et₂O (2×10 mL) and cold EtOAc (3×5 mL) to give the product as agrayish solid: m.p. 210-212° C. MS m/z: 340 (M+H). Calc'd. forC₁₇H₁₇N₅OS—339.422.

EXAMPLE 52

[0912]

[0913]N-[2-(2-Pyridinyl)-4-thiazolyl]-N′-2-[4-(1-methylethyl)pyridinyl]urea

[0914] 2-(2-Pyridinyl)-4-thiazolylcarbonylazide (300 mg, 1.3 mmol) and2-amino-4-isopropylpyridine (500 mg, 3.6 mmol) were heated in 10 mLtoluene at 100° C. for 12 h. After cooling to RT, the solvent wasremoved by rotary evaporation and the crude oil was purified by columnchromatography with hexane:EtOAc (7:3) as eluant to give the urea as alight yellow solid. MS m/z: 340 (M+H). Calc'd for C₁₇H₁₇N₅OS—339.42.

EXAMPLE 53

[0915]

[0916] N-[2-(2-Thienyl)-4-thiazolyl]-N′-2-(pyridinyl)urea

[0917] 2-(2-Thienyl)-4-thiazolylcarbonylazide (200 mg, 0.85 mmol) and2-aminopyridine (154 mg, 1.62 mmol) were heated in 20 mL toluene at 100°C. for 16 h. After cooling to RT, the solids were collected byfiltration and washed first with toluene (2×20 mL) followed byEt₂O:EtOAc (3:1) (3×10 mL) to afford the urea as an off-white solid. MSm/z: 303 (M+H). Calc'd for C₁₃H₁₀N₄OS₂—302.38.

EXAMPLE 54

[0918]

[0919] N-[3-(4-Pyridinyl)phenyl]-N′-2-(6-propylpyridinyl)urea

[0920] To a suspended anhydrous solution of 4-pyridylaniline (180 mg,1.06 mmol) in dry toluene (8 mL) was added phosgene (0.73 mL, 1.38 mmol,20% in toluene) followed by DIEA (0.37 mL, 2.11 mmol) under anatmosphere of argon. After stirring for 0.5 h at RT,2-amino-6-(n-propyl)pyridine (144 mg, 1.06 mmol) in dry toluene (3 mL)was added dropwise into the reaction mixture. The resulting mixture wasstirred at RT for 18 h. The organic solvent was removed under vacuum.The residue was purified by flash chromatography on silica gel using 5%MeOH/CH₂Cl₂ as eluant to obtain the final urea as white solid: m.p.195-198° C. MS m/z: 333.4 (M+H). Calc'd. for C₂₀H₂₀N₄O—332.405.

EXAMPLE 55

[0921]

[0922] N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-benzthiazolylurea

[0923] In a manner similar to that described in Example 2,2-(4-pyridinyl)-4-thiazolylcarbonylazide (52 mg, 0.225 mmol) and2-aminobenzothiazole (41 mg, 0.273 mmol) were heated in toluene (10 mL)to give the product as a pale yellow solid. MS m/z: 354.4 (M+H). Calc'd.for C₁₆H₁₁N₅OS₂—353.427.

EXAMPLE 56

[0924]

[0925] N-[2-(2-Thienyl)-4-thiazolyl]-N′-2-(4-ethylpyridinyl)urea

[0926] 2-(2-Thienyl)-4-thiazolylcarbonylazide (500 mg, 2.1 mmol) and2-amino-4-ethylpyridine (512 mg, 4.2 mmol) were heated in 15 mL tolueneat 100° C. for 16 h. After cooling to RT, the solids were collected byfiltration and washed first with toluene (2×20 mL) followed byEt₂O:EtOAc (3:1) (3×10 mL) to afford the urea as an off-white solid. MSm/z: 331 (M+H). Calc'd for C₁₅H₁₄N₄OS₂—330.435.

EXAMPLE 57

[0927]

[0928] N-[2-(2-Thienyl)-4-thiazolyl]-N′-2-(3-methylpyridinyl)urea

[0929] 2-(2-Thienyl)-4-thiazolylcarbonylazide (500 mg, 2.1 mmol) and2-amino-3-methylpyridine (449 mg, 4.2 mmol) were heated in 15 mL tolueneat 100° C. for 16 h. After cooling to RT, the solids were collected byfiltration and washed first with toluene (2×20 mL) followed byEt₂O:EtOAc (3:1) (3×10 mL) to afford the urea as an off-white solid. MSm/z: 317 (M+H). Calc'd for C₁₄H₁₂N₄OS₂—316.408.

EXAMPLE 58

[0930]

[0931] N-[2-(3-Thienyl)-4-thiazolyl]-N′-2-(4-ethylpyridinyl)urea

[0932] 2-(3-Thienyl)-4-thiazolylcarbonylazide (200 mg, 0.85 mmol) and2-amino-4-ethylpyridine (310 mg, 2.54 mmol) were heated in 10 mL tolueneat 100° C. for 16 h. After cooling to RT, the solids were collected byfiltration and washed first with toluene (2×20 mL) followed byEt₂O:EtOAc (3:1; (3×10 mL) to afford the product as an off-white solid.MS m/z: 331 (M+H). Calc'd for C₁₅H₁₄N₄OS₂—330.435.

EXAMPLE 59

[0933]

[0934] N-[2-(3-Thienyl)-4-thiazolyl]-N′-2-(4-methylpyridinyl)urea

[0935] 2-(3-Thienyl)-4-thiazolylcarbonylazide (200 mg, 0.85 mmol) and2-amino-4-methylpyridine (272 mg, 2.54 mmol) were heated in 10 mLtoluene at 100° C. for 16 h. After cooling to RT, the solids werecollected by filtration and washed first with toluene (2×20 mL) followedby Et₂O:EtOAc (3:1) (3×10 mL) to afford the product as an off-whitesolid. MS m/z: 317 (M+H). Calc'd for C₁₄H₁₂N₄OS₂—316.408.

EXAMPLE 60

[0936]

[0937]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(1-morpholinylmethyl)pyridinyl]urea

[0938] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (100 mg, 0.43 mmol) in drytoluene (10 mL) was heated to 85° C. under N₂ and maintained at for 5min. A solution of 6-morpholin-4ylmethyl-pyridin-2-ylamine (101 mg, 0.52mmol) in dry toluene (2 mL) was added dropwise via syringe and theresulting mixture was heated at 100° C. for 12 h. After cooling to RT, aprecipitate formed and was collected, rinsing with hexane to give awhite solid. MS m/z: 397.3 (M+H). Calc'd for C₁₉H₂₀N₆O₂S: 396.14.

[0939] The following compounds were prepared from the correspondingamines in a manner similar to that described above for Example 60.

EXAMPLE 61

[0940]

[0941] Ethyl1-{6-[3-(2-(pyridin-4-yl)thiazol-4-yl)ureido]-pyridin-2-ylmethyl}-piperidine-4-carboxylate

[0942] 2-(4-Pridinyl)-4-thiazolcarbonylazide (182 mg, 0.87 mmol) heatedwith ethyl 1-(6-aminopyridin-2-ylmethyl)-piperidine-4-carboxylate (230mg, 0.87 mmol) in dry toluene (15 mL) gave the final urea. MS m/z: 466.9(M+H). Calc'd. for C₂₃H₂₆N₆O₃S—466.50.

EXAMPLE 62

[0943]

[0944] tert-Butyl(1-hydroxymethyl-3-methyl-butyl)-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamate

[0945] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (343 mg, 1.48 mmol) washeated with2-amino-6-[N′-tert-butoxycarbonyl-N′-2-(1-hydroxy-4-methyl)pentylamino]methylpyridine(480 mg, 1.48 mmol) in dry toluene (20 mL) to yield the final compoundas pale yellow solid. MS m/z: 527.6 (M+H). Calc'd. forC₂₆H₃₄N₆O₄S—526.66.

EXAMPLE 63

[0946]

[0947]1-[6-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-thiazol-4-yl)-urea

[0948] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (420 mg, 2.01 mmol) washeated with 2-amino-6-(4-ethoxyacetal)-piperidinylmethyl pyridine (500mg, 2.01 mmol) in dry toluene (30 mL) to yield the final compound asyellow solid. MS m/z: 452.9 (M+H). Calc'd. for C₂₂H₂₄N₆O₃S—452.23.

EXAMPLE 64

[0949]

[0950]1-[6-(3,5-Dimethylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-ylthiazol-4-yl)urea

[0951] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (200 mg, 0.867 mmol) washeated with 2-amino-6-(3,5-dimethyl)piperidinyl-methylpyridine (190 mg,0.867 mmol) in dry toluene (20 mL) to yield the final compound as yellowsolid. MS m/z: 423.2 (M+H). Calc'd. for C₂₂H₂₆N₆OS—422.0.

EXAMPLE 65

[0952]

[0953]1-[6-(4-Methylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[0954] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (348 mg, 1.51 mmol) washeated with 2-amino-6-(4-methyl)piperidinyl-methylpyridine (310 mg, 1.51mmol) in dry toluene (20 mL) to yield the final compound as pale yellowsolid. MS m/z: 409.5(M+H). Calc'd. for C₂₁H₂₄N₆OS—408.52.

EXAMPLE 66

[0955]

[0956]1-[6-(2-Methylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[0957] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (101 mg, 0.44 mmol) washeated with 2-amino-6-(2-methyl)piperidinylmethyl pyridine (90 mg, 0.44mmol) in dry toluene (15 mL) to yield the final compound as pale yellowsolid. MS m/z: 409.6 (M+H). Calc'd. for C₂₁H₂₄N₆OS—408.52.

EXAMPLE 67

[0958]

[0959]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea

[0960] 2-(4-pyridinyl)-4-thiazolcarbonylazide (293 mg, 1.43 mmol) washeated with 2-amino-6-[4-(1-pyrrolidinyl)-piperidinylmethyl]pyridine(330 mg, 1.43 mmol) in dry toluene (20 mL) to yield the final compoundas pale yellow solid. MS m/z: 464.2 (M+H). Calc'd. for C₂₄H₂₉N₇OS—463.

EXAMPLE 68

[0961]

[0962]1-[6-(3-Hydroxy-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2pyridin-4-yl-thiazol-4-yl)-urea

[0963] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (312 mg, 1.35 mmol) washeated with 2-amino-6-(3-hydroxy)-piperidinylmethyl pyridine (280 mg,1.35 mmol) in dry toluene (20 mL) to yield the final compound as yellowsolid. MS m/z: 410.9 (M+H). Calc'd. for C₂₀H₂₂N₆O₂S—410.5.

EXAMPLE 69

[0964]

[0965] N-(6-azidomethyl-2-pyridyl)-N′-[2-(4-pyridinyl)-4-thiazolyl]urea

[0966] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (400 mg, 1.73 mmol) washeated with 2-amino-6-azidomethyl-pyridine (258 mg, 1.73 mmol) in drytoluene (15 mL) to yield the final compound as yellow solid. MS m/z:353.4(M+H). Calc'd. for C₁₅H₁₂N₈OS—352.38.

EXAMPLE 70

[0967]

[0968]1-[6-(2-Methyl-imidazol-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[0969] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (110 mg, 0.48 mmol) washeated with 2-amino-6-[2-methylimidazol-1-yl]methyl-pyridine (90 mg,0.48 mmol) in dry toluene (15 mL) to yield the final compound as whitesolid. MS m/z: 392.4 (M+H). Calc'd. for C₁₉H₁₇N₇OS—391.45.

EXAMPLE 71

[0970]

[0971]1-(6-Azepan-1-ylmethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[0972] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (150 mg, 0.65 mmol) and2-amino-6-azaperhydroepinylmethylpyridine (147 mg, 0.71 mmol) in drytoluene (15 mL) were heated at 100° C. for 12 h to give a pale yellowsolid. MS m/z: 409.1 (M+H). Calc'd for C₂₁H₂₄N₆OS—408.52.

EXAMPLE 72

[0973]

[0974]1-[6-(4-Hydroxy-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[0975] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (265 mg, 1.27 mmol) and2-amino-6-(4-hydroxy)piperidyl-methylpyridine (220 mg, 1.06 mmol) in drytoluene (15 mL) were heated at 100° C. for 12 h to give a pale yellowsolid which was recrystallized from CHCl₃/MeOH/hexane (94:2:1) to give awhite solid. MS m/z: 410.9 (M+H). Calc'd for C₂₀H₂₂N₆O₂S—410.50.

EXAMPLE 73

[0976]

[0977] Ethyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}piperidine-3-carboxylate

[0978] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (150 mg, 0.65 mmol) and2-amino-ethyl(6-piperidylmethyl-pyridinyl)-3-carboxylate (170 mg, 0.65mmol) in dry toluene (15 mL) were heated at 100° C. for 12 h to give apale yellow solid which was purified by chromatography on silica gel(CH₂Cl₂/MeOH, 95:5) to give a white solid. MS m/z: 467.1 (M+H). Calc'dfor C₂₃H₂₆N₆O₃S—466.56.

EXAMPLE 74

[0979]

[0980] Ethyl1-[6-[3-(2-(pyridin-4-yl)thiazol-4-yl)ureido]-pyridin-2-ylmethyl]piperidine-2-carboxylate

[0981] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (483 mg, 2.09 mmol) andethyl 2-amino-(6-piperidylmethyl-pyridinyl)-2-carboxylate (550 mg, 2.09mmol) in dry toluene (20 mL) were heated at 100° C. for 8 h to give apale yellow solid which was purified by chromatography on silica gel(CH₂Cl₂/MeOH, 95:5) to give a white solid. MS m/z: 466.9 (M+H). Calc'dfor C₂₃H₂₆N₆O₃S—466.56.

EXAMPLE 75

[0982]

[0983] N,N-Diethyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-2-ylmethyl}piperidine-3-carboxamide

[0984] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (320 mg, 1.38 mmol) and2-amino-6-[(N″,N″-diethylcarbamoyl)-piperidylmethyl]-3-carboxamide (400mg, 1.38 mmol) in dry toluene (25 mL) were heated at 100° C. for 12 h togive a pale yellow solid which was purified by chromatography on silicagel (CH₂Cl₂/MeOH, 95:5) to give the urea as a white solid. MS m/z: 494.1(M+H). Calc'd for C₂₅H₃₁N₇O₂S—493.63.

EXAMPLE 76

[0985]

[0986]1-(6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-piperidine-3-carboxylicacid

[0987] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (196 mg, 0.85 mmol) and2-amino-6-(piperidylmethylpyridinyl)-3-carboxylate (200 mg, 0.85 mmol)in dry toluene (10 mL) were heated at 100° C. for 8 h to give a paleyellow solid which was purified by chromatography on silica gel(CH₂Cl₂/MeOH, 95:5) to give a white solid. MS m/z: 437.9 (M+H). Calc'dfor C₂₁H₂₂N₆O₃S—438.51.

EXAMPLE 77

[0988]

[0989] Methyl1-(6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}-pyrrolidine-2-carboxylate

[0990] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (104 mg, 0.45 mmol) and2-amino-6-(2-methoxycarbonyl)-pyrrolidinyl-methylpyridine (105 mg, 0.45mmol) in dry toluene (10 mL) were heated at 100° C. for 12 h to give apale yellow solid which was purified by chromatography on silica gel(CHCl₃/MeOH, 99:5) to give a white solid. MS m/z: 438.7 (M+H). Calc'dfor C₂₁H₂₂N₆O₃S—438.51.

EXAMPLE 78

[0991]

[0992]1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[0993] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (259 mg, 1.12 mmol) and2-amino-6-(3-methyl)piperidinylmethyl-pyridine (230 mg, 1.12 mmol) indry toluene (15 mL) were heated at 100° C. for 12 h to give a paleyellow solid which was purified by chromatography on silica gel(CHCl₃/MeOH, 99:5) to give a white solid. MS m/z: 408.8 (M+H). Calc'dfor C₂₁H₂₄N₆OS—408.53.

EXAMPLE 79

[0994]

[0995]1-(2-Phenoxy-thiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea

[0996] MS m/z: 410 (M+H). Calc'd for C₂₁H₂₃N₅O₂S: 409.16.

EXAMPLE 80

[0997]

[0998] tert Butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-2-yloxymethyl}-azetidine-1-carboxylate

[0999] MS m/z: 483 (M+H). Calc'd for C₂₃H₂₆N₆O₄S: 482.17.

EXAMPLE 81

[1000]

[1001] tert Butyl4-(2-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-2-yloxy}ethyl)piperidine-1-carboxylate

[1002] MS m/z: 525 (M+H). Calc'd for C₂₆H₃₂N₆O₄S: 524.22

EXAMPLE 82

[1003]

[1004]1-[6-(4-Dimethylaminomethyl-phenoxymethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1005] MS m/z: 461 (M+H). Calc'd for C₂₄H₂₄N₆O₂S: 460.17.

EXAMPLE 83

[1006]

[1007]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-(4-methylphenyl)oxymethylpyridin-2-yl)urea

[1008] MS m/z: 416 (M−H). Calcld for C₂₂H₁₉N₅O₂S: 417.13.

EXAMPLE 84

[1009]

[1010] tert Butyl(2-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-2-ylmethoxy}ethyl)carbamate

[1011] MS m/z: 471 (M+H). Calc'd for C₂₂H₂₆N₆O₄S: 470.17.

EXAMPLE 85

[1012]

[1013] tert Butyl(2-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-3-ylmethoxy)ethyl)carbamate

[1014] MS m/z: 471 (M+H). Calc'd for C₂₂H₂₆N₆O₄S: 470.17.

EXAMPLE 86

[1015]

[1016]1-(5-Methoxymethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1017] MS m/z: 342 (M+H). Calc'd for C₁₆H₁₅N₅O₂S: 341.09.

EXAMPLE 87

[1018]

[1019]1-(5-Morpholin-4-ylmethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1020] MS m/z: 397 (M+H). Calc'd for C₁₉H₂₀N₆O₂S: 396.14.

EXAMPLE 88

[1021]

[1022]1-{6-[2-phthalimidylethyllpyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1023] Prepared in a manner similar to that described in Example 60 from3-(4-pyridyl)-thiazole acyl-azide (103 mg, 0.56 mmol) and2-amino-6-ethylphthalamidylpyridine (150 mg, 0.56 mmol) in toluene (10mL). Concentrated in vacuo to afford a yellow solid which was treatedwith EtOH (10 mL) and filtered to give the title compound as a yellowsolid. MS m/z: 470.9 (M+H). Calc'd for C₂₄H₁₈N₆O₃S: 470.12.

EXAMPLE 89

[1024]

[1025] 1-(6-Cyanomethylpyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1026] Prepared in a manner similar to that described in Example 60 from2-amino-6-methylnitrile-pyridine (0.32 g, 2.4 mmol) and3-(4-pyridyl)-4-thiazole acylazide (0.51 g, 2.2 mmol). After 1.5 h,yellow solid precipitated out of toluene solution. The mixture wascooled to RT and the solid filtered. Purified by silica flashchromatography (3% MeOH/CH₂Cl₂) to afford the title compound as a whitesolid. MS m/z: 337.1 (M+H). Calc'd for ClEH₁₂N₆OS: 336.08.

EXAMPLE 90

[1027]

[1028]1-[2-(2-Chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea

[1029] Prepared in a manner similar to that described in Example 60 from3-(4-pyridyl)-4-thiazole acyl azide (0.51 g, 1.9 mmol) and2-amino-6-methylmorpholino-pyridine (0.42 g, 2.2 mmol) in toluene (50mL). After 3 h, the reaction mixture was cooled to RT and filtered toafford the title compound as a light purple solid. MS m/z: 431.0 (M+H).Calcld for C₁₉H₁₉ClN₆O₂S: 430.10.

EXAMPLE 91

[1030]

[1031] 1-(6-Aminopyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1032] Prepared in a manner similar to that described in Example 60 from3-(4-pyridyl)-4-thiazole-acyl azide (148 mg, 0.64 mmol) and2,6-diaminopyridine (77 mg, 0.70 mmol, Aldrich) in toluene (10 mL).After 2 h, a yellow precipitate formed. The reaction mixture was cooledand filtered to afford the title compound as a yellow solid. MS m/z: 180(M+H). Calc'd for C₁₄H₁₂N₆OS: 312.08.

EXAMPLE 92

[1033]

[1034]1-(6-Morpholin-4-yl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1035] EI-MS m/z 383.4 (M+H). Calc'd for C₁₈H₁₈N₆O₂S: 382.12.

EXAMPLE 93

[1036]

[1037]1-[6-(2,4-Dimethylphenoxy)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1038] EI-MS m/z 418.5 (M+H). Calc'd for C₂₂H₁₉N₅O₂S: 417.13.

EXAMPLE 94

[1039]

[1040] 1-(6-Phenoxypyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1041] EI-MS m/z 390.4 (M+H). Calc'd for C₂₀H₁₅N₅O₂S: 389.09.3.

EXAMPLE 95

[1042]

[1043]1-[6-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1044] Prepared in a manner similar to that described in Example 60using 2-(4-pyridinyl)-4-thiazolcarbonylazide and the requisite2-aminopyridine. EI-MS m/z 439.5 (M+H). Calc'd for C₂₁H₂₂N₆O₃S: 438.15.

EXAMPLE 96

[1045]

[1046]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-p-tolyloxy-pyridin-2-yl)-urea

[1047] EI-MS m/z 404.4 (M+H). Calc'd for C₂₁H₁₇N₅O₂S: 403.11.

EXAMPLE 97

[1048]

[1049]1-(4-Oxo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-3(2-pyridin-4-yl-thiazol-4-yl)-urea

[1050] EI-MS m/z 395.4 (M+H). Calc'd for C₁₉H₁₈N₆O₂S: 394.12.

EXAMPLE 98

[1051]

[1052]1-(4-Benzylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-3-(2-pyridin-4-yl-thiaol-4-yl)-urea

[1053] EI-MS m/z 486.7 (M+H). Calc'd for C₂₆H₂₇N₇OS: 485.20.

EXAMPLE 99

[1054]

[1055]1-(4-Propylamino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1056] EI-MS m/z 438.6 (M+H). Calcld for C₂₂H₂₇N₇OS: 437.20.

EXAMPLE 100

[1057]

[1058]1-[4-(2-Hydroxy-ethylamino)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1059] EI-MS m/z 440.5 (M+H). Calc'd for C₂₁H₂₅N₇O₂S: 439.18.

EXAMPLE 101

[1060]

[1061]1-(4-Amino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1062] EI-MS m/z 396.6 (M+H). Calc'd for C₁₉H₂₁N₇OS: 395.15.

EXAMPLE 102

[1063]

[1064]1-[6-(4-Cyanophenoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1065] EI-MS m/z 415.5 (M+H). Calc'd for C₂₁H₁₄N₆O₂S: 414.09.

EXAMPLE 103

[1066]

[1067]1-(4-Hydroxyimino-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1068] EI-MS m/z 410.4(M+H). Calc'd for C₁₉H₁₉N₇O₂S: 409.13.

EXAMPLE 104

[1069]

[1070]1-[6-(1-Aza-bicyclo[2.2.2]oct-3-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1071] EI-MS m/z 423.6 (M+H). Calc'd for C₂₁H₂₂N₆O₂S: 422.15.

EXAMPLE 105

[1072]

[1073]1-[6-(3-Dimethylamino-pyrrolidin-1-yl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1074] EI-MS m/z 410.5 (M+H). Calc'd for C₂₀H₂₃N₇OS: 409.17.

EXAMPLE 106

[1075]

[1076]1-[6-(2-Dimethylamino-ethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1077] EI-MS m/z 385.5 (M+H). Calc'd for C₁₈H₂₀N₆O₂S: 384.14.

EXAMPLE 107

[1078]

[1079] 1-(2-Methylthiazol-4-yl)-3-(6-phenoxy-pyridin-2-yl)urea

[1080] EI-MS m/z 327.4 (M+H). Calc'd for C₁₆H₁₄N₄O₂S: 326.08.

EXAMPLE 108

[1081]

[1082]1-[6-(1-Methylpyrrolidin-2-ylmethoxy)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1083] EI-MS m/z 411.4 (M+H). Calc'd for C₂₀H₂₂N₆O₂S: 410.15.

EXAMPLE 109

[1084]

[1085]1-[6-(4-Imidazol-1-yl-phenoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1086] EI-MS m/z 456.6 (M+H). Calc'd for C₂₃H₁₇N₇O₂S: 455.12.

EXAMPLE 110

[1087]

[1088] 1-(6-Phenoxypyridin-2-yl)-3-(2-pyridin-3-yl-thiazol-4-yl)urea

[1089] EI-MS m/z 390.5 (M+H). Calc'd for C₂₀H₁₅N₅O₂S: 389.09.

EXAMPLE 111

[1090]

[1091]1-[6-(4-[1,3]Dioxolan-2-yl-phenoxy)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1092] EI-MS m/z 462.5 (M+H). Calc'd for C₂₃H₁₉N₅O₄S: 461.12.

EXAMPLE 112

[1093]

[1094]1-[6-(4-Fluorophenoxy)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1095] EI-MS m/z 408.5 (M+H). Calc'd for C₂₀H₁₄FN₅O₂S: 407.09.

EXAMPLE 113

[1096]

[1097]1-[6-(3,4-Difluorophenoxy)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1098] EI-MS m/z 426.5 (M+H). Calc'd for C₂₀H₁₃F₂N₅O₂S: 425.08.

EXAMPLE 114

[1099]

[1100]1-{6-[4-(2-Aminoethyl)phenoxy]pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1101] EI-MS m/z 433.5 (M+H). Calc'd for C₂₂H₂₀N₆O₂S: 432.14.

EXAMPLE 115

[1102]

[1103] 1-Pyridin-3-yl-3-(2-pyridin-3-yl-thiazol-4-yl)-urea

[1104] EI-MS m/z 396.6 (M+H). Calc'd for C₁₄H₁₁N₅OS: 297.07.

EXAMPLE 116

[1105]

[1106] 6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridine-2-carbothioicacid methylamide

[1107] EI-MS m/z 371.5 (M+H). Calc'd for C₁₆H₁₄N₆OS₂: 370.07.

EXAMPLE 117

[1108]

[1109]1-(6-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1110] EI-MS m/z 383.5 (M+H). Calc'd for C₁₉H₂₂N₆OS: 382.16.

EXAMPLE 118

[1111]

[1112]1-(6-Methylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1113] EI-MS m/z 341.4 (M+H). Calc'd for C₁₆H₁₆N₆OS: 340.11.

EXAMPLE 119

[1114]

[1115]1-[6-(3-Morpholin-4-yl-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1116] EI-MS m/z 440.4 (M+H). Calc'd for C₂₁H₂₅N₇O₂S: 439.18.

EXAMPLE 120

[1117]

[1118]1-[6-(2-Dimethylamino-ethylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1119] EI-MS m/z 384.5 (M+H). Calc'd for C₁₈H₂₁N₇OS: 383.15.

EXAMPLE 121

[1120]

[1121]1-(6-Diethylamino-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1122] EI-MS m/z 369.3 (M+H). Calc'd for C₁₈H₂₀N₆OS: 368.14.

EXAMPLE 122

[1123]

[1124] 6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]nicotinamide

[1125] EI-MS m/z 341.3 (M+H). Calc'd for C₁₅H₁₂N₆O₂S: 340.07.

EXAMPLE 123

[1126]

[1127] 4-{4-[3-(6-Propylpyridin-2-yl)ureido]thiazol-2-yl)-benzensulfonamide

[1128] EI-MS m/z 418.5 (M+H). Calc'd for C₁₈H₁₉N₅O₃S₂: 417.09.

EXAMPLE 124

[1129]

[1130] tert Butyl(4-{4-[3-(6-Propylpyridin-2-yl)ureido]-thiazol-2-yl}phenyl)carbamate

[1131] EI-MS m/z 454.6 (M+H). Calc'd for C₂₃H₂₇N₅O₃S: 453.18.

EXAMPLE 125

[1132]

[1133] 2-Dimethylaminoethyl6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]pyridine-2-carboxamide

[1134] EI-MS m/z 412.5 (M+H). Calc'd for C₁₉H₂₁N₇O₂S: 411.15.

EXAMPLE 126

[1135]

[1136] 1-[6-(4-Ethylpiprazin-1-yl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1137] EI-MS m/z 410.6 (M+H). Calc'd for C₂₀H₂₃N₇OS: 409.17.

EXAMPLE 127

[1138]

[1139]1-{2-[4-(4-Morpholinylsulfonyl)phenyl]thiazol-4-yl}-3-(6-propyl-pyridin-2-yl)urea

[1140] EI-MS m/z 488.7 (M+H). Calc'd for C₂₂H₂₅N₅O₄S₂: 487.13.

EXAMPLE 128

[1141]

[1142] 1-[2-(4-Aminophenyl) thiazol-4-yl]-3-(6-propylpyridin-2-yl)urea

[1143] EI-MS m/z 354.4 (M+H). Calc'd for C₁₈H₁₉N₅OS: 353.13.

EXAMPLE 129

[1144]

[1145]1-[6-(4-Benzylpiperazin-1-yl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1146] EI-MS m/z 472.5 (M+H). Calc'd for C₂₅H₂₅N₇OS: 471.18.

EXAMPLE 130

[1147]

[1148]1-[6-(4-Methyl-piperazin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1149] EI-MS m/z 410.5 (M+H). Calc'd for C₂₀H₂₃N₇OS: 409.17.

EXAMPLE 131

[1150]

[1151]1-(6-Hydroxymethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1152] EI-MS m/z 328.4 (M+H). Calc'd for C₁₅H₁₃N₅O₂S: 327.08.

EXAMPLE 132

[1153]

[1154] Diethyl6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureidol-pyridine-2-carboxamide

[1155] EI-MS m/z 397.6 (M+H). Calc'd for C₁₉H₂₀N₆O₂S: 396.14.

EXAMPLE 133

[1156]

[1157]1-[6-(4-Methylpiperazin-1-yl)pyridin-2-yl]-3-(2-pyridin-3-yl-thiazol-4-yl)urea

[1158] EI-MS m/z 396.5 (M+H). Calc'd for C₁₉H₂₁N₇OS: 395.15.

EXAMPLE 134

[1159]

[1160]1-(6-Piperidin-1-ylmethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1161] EI-MS m/z 395.6 (M+H). Calc'd for C₂₀H₂₂N₆OS: 394.16.

EXAMPLE 135

[1162]

[1163] 6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridine-2-carboxylicacid ethyl ester

[1164] EI-MS m/z 370.4 (M+H). Calc'd for C₁₇H₁₅N₅O₃S: 369.09.

EXAMPLE 136

[1165]

[1166]1-[6-(Piperidine-1-carbonyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1167] EI-MS m/z 409.5 (M+H). Calc'd for C₂₀H₂₀N₆O₂S: 408.14.

EXAMPLE 137

[1168]

[1169]1-[6-(4-Methylpiperazin-1-yl)pyridin-2-yl]-3-(2-pyrimidin-4-yl-thiazol-4-yl)urea

[1170] EI-MS m/z 397.5 (M+H). Calc'd for C₁₈H₂₀N₈OS: 396.15.

EXAMPLE 138

[1171]

[1172]1-(6-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyrimidin-4-yl-thiazol-4-yl)urea

[1173] EI-MS m/z 384.6 (M+H). Calc'd for C₁₈H₂₁N₇OS: 383.15.

EXAMPL 139

[1174]

[1175]1-(6-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-3-yl-thiazol-4-yl)urea

[1176] EI-MS m/z 383.5 (M+H). Calc'd for C₁₉H₂₂N₆OS: 382.16.

EXAMPLE 140

[1177]

[1178] Methyl6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]pyridine-2-carboxamide

[1179] EI-MS m/z 355.3 (M+H). Calc'd for C₁₆H₁₄N₆O₂S: 354.09.

EXAMPLE 141

[1180]

[1181] 1-[6-(Pip ridin-1-carbonyl)pyridin-2-yl]-3-(2-pyridin-3-yl-thiazol-4-yl)urea

[1182] EI-MS m/z 409.5 (M+H). Calc'd for C₂₀H₂₀N₆O₂S: 408.14.

EXAMPLE 142

[1183]

[1184]1-(6-Ethylaminomethylpyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1185] EI-MS m/z 355.5 (M+H). Calc'd for C₁₇H₁₈N₆OS: 354.13.

EXAMPLE 143

[1186]

[1187] Ethyl6-[3-(2-Pyridin-4-yl-thiazol-4-yl)ureido]pyridine-2-carboxamide

[1188] EI-MS m/z 369.4 (M+H). Calc'd for C₁₇H₁₆N₆O₂S: 368.11.

EXAMPLE 144

[1189]

[1190] Ethyl6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridine-2-thiocarboxamide

[1191] EI-MS m/z 385.5 (M+H). Calc'd for C₁₇H₁₆N₆OS₂: 384.08.

EXAMPLE 145

[1192]

[1193]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(4-pyrimidin-2-yl-piperazin-1-yl)pyridin-2-yl]urea

[1194] EI-MS m/z 460.5 (M+H). Calc'd for C₂₂H₂₁N₉OS: 459.16.

EXAMPLE 146

[1195]

[1196]1-(6-Piperidin-1-ylmethyl-pyridin-2-yl)-3-(2-pyridin-3-yl-thiazol-4-yl)-urea

[1197] EI-MS m/z 395.5 (M+H). Calc'd for C₂₀H₂₂N₆OS: 394.16.

EXAMPLE 147

[1198]

[1199]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-pyrrolidin-1-ylmethyl-pyridin-2-yl)-urea

[1200] EI-MS m/z 381.5 (M+H). Calc'd for C₁₉H₂₀N₆OS: 380.14.

EXAMPLE 148

[1201]

[1202] 1-[1,6]Naphthyridin-2-yl-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1203] EI-MS m/z 349.5 (M+H). Calc'd for C₁₇H₁₂N₆OS: 348.08.

EXAMPLE 149

[1204]

[1205]1-[6-(4-Pyridin-2-yl-piperazin-1-yl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1206] EI-MS m/z 459.5 (M+H). Calc'd for C₂₃H₂₂N₈OS: 458.16.

EXAMPLE 150

[1207]

[1208]1-[6-(4-Pyridin-2-yl-piperazin-1-yl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1209] EI-MS m/z 459.5 (M+H). Calc'd for C₂₃H₂₂N₈OS: 458.16.

EXAMPLE 151

[1210]

[1211]1-(6-Propyl-5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1212] EI-MS m/z 395.6 (M+H). Calc'd for C₂₀H₂₂N₆OS: 394.16.

EXAMPLE 152

[1213]

[1214]1-(6-Ethyl-5,6,7,8-tetrahydro-[1,6]naphthyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1215] EI-MS m/z 381.5(M+H). Calc'd for C₁₉H₂₀N₆OS: 380.14.

EXAMPLE 153

[1216]

[1217]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(1-morpholinylmethyl)pyridinyl]ureahydrochloride

[1218] To a solution ofN-[2-(pyridin-4-yl)-4-thiazolyl]-N′-2-(6-morpholinylmethylpyridinyl)urea(90 mg, 0.23 mmol, Example 60) in MeOH (3 mL) was added HCl (0.25 mL,0.25 mmol, 1.0 M in Et₂O). The resulting mixture was stirred at RT for 2h then concentrated in vacuo to give a pale yellow solid.

[1219] The following Examples 154-165 were prepared from thecorresponding amines in a manner similar to that described above forExample 153.

EXAMPLE 154

[1220]

[1221] Ethyl1-(6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl)-piperidine-4-carboxylatehydrochloride

[1222] Ethyl1-(6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-piperidine-4-carboxylate(50 mg, 0.05 mmol, Example 61) in MeOH (5 mL) was treated with HCl (0.12mL, 0.06 mmol, 1M in Et₂O) to afford the title salt as a yellow solid.

EXAMPLE 155

[1223]

[1224]1-[6-(3,5-Dimethylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-ylthiazol-4-yl)ureahydrochloride

[1225]1-[6-(3,5-Dimethylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-ylthiazol-4-yl)urea(52 mg, 0.123 mmol, Example 64) was treated with HCl (0.08 mL, 0.135mmol, 1 M in Et₂O) to afford the title salt as a yellow solid.

EXAMPL 156

[1226]

[1227]1-[6-(4-Oxo-piperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)ureahydrochloride

[1228]1-[6-(4-Oxo-piperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea(30 mg, 0.073 nmmol, Example 175) was treated with HCl (0.08 mL, 0.081mmol, 1M in Et₂O) to afford the title salt as a yellow solid.

EXAMPLE 157

[1229]

[1230]1-[6-(4-Methylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)ureahydrochloride

[1231]1-[6-(4-Methylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea(70 mg, 0.171 mmol, Example 65) was treated with HCl (0.19 mL., 0.188mmol, 1M in Et₂O) to afford the title salt as a yellow solid.

EXAMPLE 158

[1232]

[1233]1-[6-(2-Methylpiperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)ureahydrochloride

[1234]1-[6-(2-Methylpiperidin-1-ylmethyl)pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea(70 mg, 0.171 mmol, Example 66) was treated with HCl (0.19 mL, 0.188mmol, 1M in Et₂O) to afford the title salt as a yellow solid.

EXAMPLE 159

[1235]

[1236] Ethyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}piperidine-3-carboxylatehydrochloride

[1237] HCl (0.21 mL, 0.212 nmuol, 1.0 M soln in Et₂O) was added to ethyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}piperidine-3-carboxylate(90 mg, 0.193 mmol, Example 73) in a solution of MeOH (2 mL) to give apale yellow solid.

EXAMPLE 160

[1238]

[1239]1-(6-Azepan-1-ylmethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)ureahydrochloride

[1240] HCl (0.29 mL, 0.28 mmol, 1.0 M soln in Et₂O) was added to1-(6-azepan-1-ylmethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea(106 mg, 0.26 mmol, Example 71) in a solution of MeOH (4 mL) and theresulting mixture stirred 6 h. Concentration in vacuo gave a yellowsolid.

EXAMPLE 161

[1241]

[1242]1-(6-Diethylaminomethyl-pyridin-2-yl)-3-(2-piperidin-4-yl-thiazol-4-yl)ureahydrochloride

[1243] HCl (27

L, 0.026 mmol, 1.0 M soln in Et₂O) was added to1-(6-diethylaminomethyl-pyridin-2-yl)-3-(2-piperidin-4-yl-thiazol-4-yl)urea(11 mg, 0.026 mmol, Example 179) in a solution of MeOH (1 mL) and theresulting mixture stirred 3 h. Concentration in vacuo gave a yellowsolid.

EXAMPLE 162

[1244]

[1245]1-[5-Bromo-2-(pyridin-4-yl)thiazol-4-yl)-3-(6-diethylaminomethyl-pyridin-2-yl)ureahydrochloride

[1246] HCl (54

L, 0.054 mmol, 1.0 M soln in Et₂O) was added to1-[5-bromo-2-(pyridin-4-yl)thiazol-4-yl)-3-(6-diethylaminomethyl-pyridin-2-yl)urea(25 mg, 0.054 mmol, Example 180) in a solution of MeOH (0.5 mL) to givea yellow solid.

EXAMPLE 163

[1247]

[1248] Ethyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-piperidine-2-carboxylatehydrochloride

[1249] HCl (0.12 mL, 0.12 nmuol, 1.0 M soln in Et₂O) was added to ethyl1-[6-[3-(2-(pyridin-4-yl)thiazol-4-yl)ureido]-pyridin-2-ylmethyl]piperidine-2-carboxylate(50 mg, 0.11 mmol, Example 74) in a solution of MeOH (2 mL) to give apale yellow solid.

EXAMPLE 164

[1250]

[1251] N,N-Diethyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-2-ylmethyl)piperidine-3-carboxamidehydrochloride

[1252] HCl (0.15 mL, 0.156 mmol, 1.0 M soln in Et₂O) was added toN,N-diethyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-2-ylmethyl)piperidine-3-carboxamide(70 mg, 0.142 mmol, Example 75) in a solution of MeOH (3 mL) to give apale yellow solid.

EXAMPLE 165

[1253]

[1254]1-[6-(Morpholin-4-ylmethyl)-pyridin-2-yl]-3-[(2-pyridin-3-yl)thiazol-4-yl]ureahydrochloride

[1255] HCl (55 □L, 0.05 mmol, 1.0 M in Et₂O) was added to1-[6-(morpholin-4-ylmethyl)-pyridin-2-yl]-3-[(2-pyridin-3-yl)thiazol-4-yl]urea(20 mg, 0.05 mmol, Example 180) in a solution of MeOH (1 mL) and theresulting mixture stirred 3 h. Concentration in vacuo gave a yellowsolid.

[1256] The following Examples 166-167 were prepared from thecorresponding protected amines in a manner similar to that describedabove for Example 157:

EXAMPLE 166

[1257]

[1258]1-[6-(Azetidin-3-ylmethoxy)pyridin-2-yl]-3-[2-(pyridin-4-yl)thiazol-4-yl]urea

[1259] From tert butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-azetidine-1-carboxylate(Example 80) EI-MS m/z 382.2 (M+H). Calc'd for C₁₈H₁₈N₆O₂S: 382.12.

EXAMPLE 167

[1260]

[1261]1-[6-(2-Piperidin-4-yl-ethoxy)pyridin-2-yl]-3-[2-(pyridin-4-yl)thiazol-4-yl]urea

[1262] From tert-butyl4-(2-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]pyridin-2-yloxy}ethyl)piperidine-1-carboxylate(Example 81) MS m/z: 425 (M+1)⁺. Calc'd for C₂₁H₂₄N₆O₂S: 424.17.

EXAMPLE 168

[1263]

[1264] N-[2-(3-Pyridinyl)-4-thiazolyl]-N′-2-[6-aminopyridin-2-yl]urea

[1265] TEA (0.27 mL, 1.94 mmol) was added to a solution of2-(pyridin-3-yl)thiazole-4-carboxylic acid (200 mg, 0.97 mmol) and 4Amolecular sieves in THF (25 mL) under N₂ at RT. (PhO)₂PON₃ (0.33 mL,1.55 mmol) followed by 2,6-diaminopyridine (265 mg, 2.43 mmol) was addedand the resulting mixture was heated at reflux for 12 h. After coolingto RT, the heterogeneous mixture was decanted to remove the molecularsieves. The precipitate was collected, rinsing with EtOAc to give alight tan solid. MS m/z: 313.0 (M+H). Calc'd for C₁₄H₁₂N₆OS: 312.08.

[1266] The following compounds were prepared from the correspondingamines in a manner similar to that described above for Example 168:

EXAMPLE 169

[1267]

[1268]1-[2-(2,6-Dichloropyridin-4-yl)thiazol-4-yl]-3-[6-(piperidin-1-ylmethyl)pyridin-2-yl]urea

[1269] 2-(2,6-Dichloropyridin-4-yl)thiazol-4-carboxylic acid (100 mg,0.36 mmol), 2-amino-6-piperidinylmethyl-pyridine (76 mg, 0.39 mmol),(PhO)₂PON₃ (0.1 mL, 0.55 mmol), and TEA (0.08 mL, 0.55 mmol) were heatedin toluene (15 mL) to yield the title compound as white solid. MS m/z:464.3 (M+H). Calc'd. for C₂₀H₂₀Cl₂N₆OS—463.39.

EXAMPLE 170

[1270]

[1271]1-[6-(Piperidin-1-ylmethyl)pyridin-2-yl]-3-[2-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]thiazol-4-yl]urea

[1272] 2-(4-Trifluoroethoxypyridin-4-yl)thiazolyl-4-carboxylic acid (150mg, 0.49 mmol), 2-amino-6-piperidinylmethyl-pyridine (104 mg, 0.54mmol), (PhO)₂PON₃ (0.16 mL, 0.74 mmol), and TEA (0.1 mL, 0.74 mmol) wereheated in toluene (15 mL) to yield the title compound as white solid. MSm/z: 493.6 (M+H). Calc'd. for C₂₂H₂₃F₃N₆O₂S—492.52.

EXAMPLE 171

[1273]

[1274]1-[6-(2-Methylimidazol-1-ylmethyl)pyridin-2-yl]-3-[2-(pyridin-3-yl)thiazol-4-yl]urea

[1275] 2-(Pyridin-3-yl)-4-thiazole-4-carboxylic acid (75 mg, 0.36 mmol),2-amino-6-[2-methylimidazol-1-yl]methyl-pyridine (75 mg, 0.40 mmol),(PhO)₂PON₃ (0.12 mL, 0.54 mmol), and TEA (0.1 mL, 0.54 mmol) were heatedin toluene (15 mL) to yield the title compound as light brown solid. MSm/z: 392.3 (M+H). Calc'd. for C₁₉H₁₇N₇OS—391.45.

EXAMPLE 172

[1276]

[1277]1-[6-(Morpholin-4-ylmethyl)-pyridin-2-yl]-3-[(2-pyridin-3-yl)thiazol-4-yl]urea

[1278] TEA (0.27 mL, 1.94 mmol) was added to a solution of2-(pyridin-3-yl)thiazole-4-carboxylic acid (200 mg, 0.97 mmol) and 4Amolecular sieves in THF (25 mL) under N₂ at RT. (PhO)₂PON₃ (0.33 mL,1.55 mmol) followed by 2-amino, 6-morpholinylmethylpyridine (280 mg,1.45 mmol) was added and the resulting mixture was heated at reflux for12 h. After cooling to RT, the heterogeneous mixture was decanted toremove the molecular sieves. The precipitate was collected, rinsed withEtOAc and purified by chromatography on silica gel (CH₂Cl₂/MeOH, 95:5)to give a white solid. MS m/z: 397.1 (M+H). Calc'd forC₁₉H₂₀N₆O₂S—396.47.

EXAMPLE 173

[1279]

[1280] 1-{6-[3-(2-(4-Pyridinyl)-4-thiazolyl)ureido]-pyridin-2-ylmthyl)-piperidine-4-carboxylic acid

[1281] Ethyl1-{6-[3-(2-(pyridin-4-yl)thiazol-4-yl)ureido]-pyridin-2-ylmethyl)-piperidine-4-carboxylate(55 mg, 0.12 mmol, Example 61) was suspended in MeOH (10 ml) followed byadding LiOH (50 mg, 1.18 mmol) in H₂O (1 ml). The resulting mixture washeated at 45° C. for 15 h. After cooling to RT, the solvent was removed.The residue was suspended in H₂O (20 mL). The pH was adjusted to 7 usingHCl (1N). The resulting mixture was extracted with CHCl₃:IpOH (3:1). Theorganic layer was washed with H₂O and brine. After being dried overanhydrous MgSO₄, the solvent was removed in vacuo to yield the finalcompound as light yellow solid. MS m/z: 438.7 (M+H). Calc'd. forC₂₁H₂₂N₆O₃S—438.51.

EXAMPLE 174

[1282]

[1283]1-{6-[(1-Hydroxymethyl-3-methylbutylamino)methyl]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1284] tert-Butyl(1-hydroxymethyl-3-methyl-butyl)-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamate(165 mg, 0.313 mmol, Example 62) in MeOH (5 mL) was treated with HCl(0.16 mL, 0.627 mmol, 4M in dioxane). The resulting stirred solution washeated at 40° C. in a closed system for 15 h. After cooling to RT, thepH was adjusted to 7 using 1 N NaOH. Solvent was removed and the residuewas extracted with CHCl₃. The organic layer was washed with H₂O, brine,dried over MgSO₄, and concentrated to yield a brown liquid crudeproduct. This crude product was purified by chromatography on silicagel. Elution with CH₂Cl₂:MeOH mixture (95:5) gave the final compound asa tan solid. MS m/z: 427.2 (M+H). Calc'd. for C₂₁H₂₆N₆O₂S—426.54.

EXAMPLE 175

[1285]

[1286]1-[6-(⁴-Oxo-piperidin-1-ylmethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1287]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(4-ethoxyacetal)piperidylmethyl]urea(300 mg, 0.66 mmol) in THF (15 mL) was treated with 5N HCl (5 mL). Theresulting mixture was heated to reflux under N₂ for 5 h. After coolingto RT, the mixture was basified using 5 N NaOH. Solvent was removed andthe residue was extracted with CHCl₃. The organic layer was washed withH₂O, brine, dried over MgSO₄, and concentrated to yield a pale yellowsolid.

[1288] MS m/z: 409.3(M+H). Calc'd. for C₂₀H₂₀N₆O₂S—408.32.

EXAMPLE 176

[1289]

[1290]1-[6-[4-(Propylamino)piperidin-1-ylmethyl]pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1291] To a suspension ofN-[2-(4-pyridinyl)-4-thiazolyl]-N′-2-[6-(piperidon-4-yl)methyl]urea (50mg, 0.12 mmol, Example 175) in MeOH (10 mL) was added propylamine (0.1mL, 1.22 mmol). The resulting mixture was heated at 50° C. for 4 h underN₂. After the mixture was cooled to RT, NaBH₄ (83 mg, 2.20 mmol) wasadded. The mixture was stirred at RT under N₂ for 3 h. Solvent wasremoved in vacuo and the crude product was purified by chromatography onsilica gel. Elution with CH₂Cl₂:MeOH (90:10) gave the title compound asa white solid. MS m/z: 451.7 (M+H). Calc'd. for C₂₃H₂₉N₇OS—451.6.

EXAMPLE 177

[1292]

[1293]1-{6-[4-(2-Hydroxyethylamino)piperidin-1-ylmethyl]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1294]N-[2-(4-Pyridinyl)-4-thiazolyl]-N′-2-[6-(piperidon-4-yl)methyl]urea (60mg, 0.147 mmol, Example 175) and ethanolamine (0.09 mL, 1.47 mmol) wereheated in MeOH (10 mL) yielded the title compound as pale yellow solid.MS m/z: 454.6 (M+H). Calc'd. for C₂₂H₂₇N₇O₂S—453.57.

EXAMPLE 178

[1295]

[1296] N-(6-Aminomethyl-2-pyridyl)-N′-[2-(4-pyridinyl)-4-thiazolyl]urea

[1297] Pd(OH)₂ (70 mg, 0.5 mmol) was suspended in EtOH (5 mL) followedby addingN-(6-azidomethyl-2-pyridyl)-N′-[2-(4-pyridinyl)-4-thiazolyl]urea (70 mg,0.198 mmol, Example 69) in EtOH (8 mL). The resulting mixture was heatedat 45° C. under H₂ balloon for 3 h. After cooling to RT, the mixture wasfiltered by passing through 2 layers of pleated filtered papers. Solventwas removed in vacuo to yield the final compound as a yellow solid. MSm/z: 327.3 (M+H). Calc'd. for C₁₅H₁₄N₆OS—326.38.

EXAMPLE 179

[1298]

[1299]1-(6-Diethylaminomethyl-pyridin-2-yl)-3-(2-piperidin-4-yl-thiazol-4-yl)urea

[1300] Lithium triethylborohydride (0.84 mL, 0.84 mmol, 1.0 M in THF)was added to a solution of1-(6-diethylamino-methyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea(100 mg, 0.24 mmol, Example 117) and DIEA (63

L, 0.36 mmol) in THF (5 mL) and the resulting mixture was stirred 6 h atRT. The reaction was quenched via dropwise addition of MeOH andconcentrated in vacuo. Purification by preparative HPLC (5-60%CH₃CN/H₂O) gave a white solid. MS m/z: 389.2 (M+H). Calc'd forC₁₉H₂₈N₆OS—388.53.

EXAMPLE 180

[1301]

[1302]1-[5-Bromo-2-(pyridin-4-yl)thiazol-4-yl)-3-(6-diethylaminomethyl-pyridin-2-yl)urea

[1303] Bromine (46

L, 0.90 mmol) was added to a solution of1-(6-diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea(190 mg, 0.45 mmol, Example 117) in MeOH (8 mL) and the resultingsolution was stirred at RT for 1 h. The reaction was quenched withsaturated sodium bisulfite solution and concentrated in vacuo. Theresidue was dissolved in CHCl₃/IpOH (3/1, 10 mL) and washed with H₂O(3×10 mL) followed by 1N NaOH solution (10 mL). The organics werecombined, dried over Na₂SO₄, and concentrated in vacuo to give a yellowsolid. MS m/z: 461.1 (M+H). Calc'd for C₁₉H₂₁BrN₆OS—461.39.

EXAMPLE 181

[1304]

[1305]1-{6-[(3-Hydroxypropylamino)methyl]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1306] Step A

[1307] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (220 mg, 0.78 mmol) and2-amino-6-[(N″-tert-butoxycarbonyl-N″-3-hydroxypropyl)amino]methylpyridine(196 mg, 0.94 mmol) in dry toluene (10 mL) were heated at 100° C. for 12h to give a pale yellow solid which was purified by chromatography onsilica gel (CH₂Cl₂/MeOH, 95:5) to giveN-[2-(pyridin-4-yl)-4-thiazolyl]-N′-2-[6-(N″-tert-butoxycarbonyl-N″-(3-hydroxypropyl)-amino]methyl-pyridinylurea as a white solid. MS m/z: 485.2 (M+H). Calc'd forC₂₃H₂₈N₆O₄S—484.58.

[1308] Step B

[1309] HCl (112

L, 0.112 mmol, 1.0 M in Et₂O) was added to a solution ofN-[2-(pyridin-4-yl)-4-thiazolyl]-N′-2-[6-(N″-tert-butoxycarbonyl-N″-(3-hydroxypropyl)-amino]methylpyridinylurea (25 mg, 0.051 mmol, Step A) in MeOH (1 mL) and the resultingmixture was heated at 45° C. for 12 h. A yellow precipitate formed andwas filtered off, rinsing with hexane. The precipitate was added toCH₂Cl₂ (15 mL) and washed with 1N NaOH solution (5 mL). The organicswere collected, dried over Na₂SO₄ and concentrated in vacuo to give apale yellow solid. MS m/z: 385.0 (M+H). Calc'd for C₁₈H₂₀N₆O₂S—384.62.

EXAMPLE 182

[1310]

[1311]1-[6-(2-Hydroxymethylpyrrolidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1312] LiAlH₄ (3 mg, 0.079 mmol) was added to a solution of methyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl)-pyrrolidine-2-carboxylate(15 mg, 0.034 mmol, Example 77) in THF (5 mL) at RT and the resultingmixture was stirred for 8 h. A precipitate formed and was collected. Thesolid was dissolved in CHCl₃ (5 mL) and washed with saturated NaHCO₃solution (5 mL). The aqueous layer was adjusted to pH 7 with lN HCl andextracted with CHCl₃. The organics were combined, dried over MgSO₄ andconcentrated in vacuo to give a pale yellow solid. MS m/z: 411.1 (M+H).Calc'd for C₂₀H₂₂N₆O₂S—410.50.

EXAMPLE 183

[1313]

[1314]1-{6-[3-(2-Pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}-pyrrolidine-2-carboxylicacid

[1315] A 1.0 N NaOH solution (0.40 mL) was added to a solution of methyl1-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]-pyridin-2-ylmethyl}pyrrolidine-2-carboxylate(3 mg, 6.84

M, Example 77) in MeOH (1 mL) and the resulting mixture was stirred atRT for 12 h. The mixture was adjusted to pH 7 with 1N HCl solution andconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ and a fewdrops of MeOH. A precipitate formed and was collected to give a whitesolid. MS m/z: 423.5 (M−H) Calc'd for C₂₀H₂₀N₆O₃S—424.48.

EXAMPLE 184

[1316]

[1317]1-(5-Bromo-(2-pyridin-4-yl)thiazol-4-yl)-3-(6-methylpyridin-2-yl)urea

[1318] NBS (686 mg, 3.85 mmol) and AIBN (158 mg, 0.96 mmol) were addedto a heterogeneous solution of1-((2-pyridin-4-yl)thiazol-4-yl)-3-(6-methylpyridin-2-yl)urea (600 mg,1.93 mmol, Example 6) in CCl₄ (25 mL) and the resulting mixture washeated at reflux for 2 h. After cooling to RT, a precipitate formed andwas collected, rinsing with hexane to give a white solid. MS m/z: 392.0(M+2H). Calc'd for C₁₅H₁₂BrN₅OS—390.26.

EXAMPLE 185

[1319]

[1320]4-{4-[3-(6-Propyl-pyridin-2-yl)-ureido]-thiazol-2-yl}-benzenesulfonamide

[1321] In an oven-dried, 50-mL, round-bottomed flask were placed2-(p-sulfamoylphenyl)thiazole-4-carboxylic acid (250 mg, 0.82 mmol),molecular sieves (800 mg) in THF (20 mL). To this mixture was added Et₃N(0.23 mL, 1.64 mmol), followed by DPPA (0.28 mL, 1.28 mmol). Thereaction was stirred for 5 min, then 6-propylpyridine-2-amine (280 mg,2.06 mmol) was added. The suspension was heated to 75° C. for 14 h,cooled to RT, diluted with H₂O (10 mL) and EtOAc (150 mL), and filteredto remove molecular sieves. The filtrate was concentrated in vacuo togive the crude product as a yellow solid which was filtered, washed withH₂O (3×10 mL), EtOAc (1×10 mL) and Et₂O (3×10 mL) to afford the titlecompound as a yellow solid. MS m/z: 418 (M+H). Calc'd for C₁₈H₁₉N₅O₃S₂:417.09.

EXAMPLE 186

[1322]

[1323]1-{2-[4-(4-Morpholinylsulfonyl)phenyl]thiazol-4-yl}-3-(6-propylpyridin-2-yl)urea

[1324] In a manner similar to that described for the preparation ofExample 185, 2-[(4-morpholinylsulfonyl)-phenyl]thiazole-4-carboxylicacid (354 mg) was treated with DPPA and 6-propylpyridine-2-amine to givethe title compound. MS m/z: 488 (M+H). Calc'd for C₂₂H₂₅N₅O₄S₂: 487.13.

EXAMPLE 187

[1325]

[1326] tert-Butyl(4-{4-[3-(6-propylpyridin-2-yl)ureido]-thiazol-2-yl}phenyl)carbamate

[1327] In a manner similar to that described for the preparation ofExample 185, 2-[4-[N-Boc-amino]-phenyl]-thiazole-4-carboxylic acid (130mg) was treated with DPPA and 6-propylpyridine-2-amine to give the titlecompound. MS m/z: 454.5 (M+H). Calc'd for C₂₃H₂₇N₅O₃S: 453.18.

EXAMPLE 188

[1328]

[1329] 1-[2-(4-Aminophenyl)thiazol-4-yl]-3-(6-propylpyridin-2-yl)urea

[1330] In an oven-dried, 25-mL, round-bottomed flask were placedN-[6-propylpyridine]-N′-[4-[N-Bocamino]pheny]-4-thiazolyl]urea (55 mg,0.12 mmol, Example 187), thioanisole (0.35 mL) in CH₂Cl₂ (10 mL)). TFA(0.35 mL) was added, the mixture was stirred at RT for 6 h thenconcentrated in vacuo. Purification by flash chromatography on silicagel [EtOAc/hexane (extracted with aq. NH₄OH), 40:60] afforded the titlecompound. MS m/z: 354.0 (M+H). Calc'd for C₁₈H₁₉N₅OS: 353.13.

EXAMPLE 189

[1331]

[1332]1-{6-[2-(1-Methylpiperidin-4-yl)ethoxy]pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1333] A mixture ofN-[2-(4-pyridinyl)-4-thiazolyl]-N′-2-[6-(4-piperidinylethoxy)pyridinyl]urea(0.17 g, 0.40 mmol, Example 167), paraformaldehyde (0.17 g), andNaBH(OAc)₃ (0.21 g, 1.0 mmol) in 40 mL of CH₂Cl₂ was stirred at RT underN₂ for 12 h. After 12 h, the solvent was removed in vacuo, and theresidue was diluted with 20 mL of H₂O, then extracted with CHCl₃/IpOH(3:1, 3×20 mL). The combined organic portions were washed with brine,and dried over MgSO₄, and the solvents were removed in vacuo to yield aresidue. Purification over silica gel (gradient, 5% to 7.5% MeOH/CH₂Cl₂with 0.5% of TEA) provided the title compound as an off-white solid. MSm/z: 439 (M+H). Calc'd for C₂₂H₂₆N₆O₂S: 438.18.

EXAMPLE 190

[1334]

[1335]1-[6-(2-Aminoethoxymethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1336] Prepared in a manner similar to that described in Example 189. MSm/z: 371 (M+H). Calc'd for C₁₇H₁₈N₆O₂S: 370.12.

EXAMPLE 191

[1337]

[1338]1-[5-(2-Aminoethoxymethyl)pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1339] Prepared in a manner similar to that described in Example 189. MSm/z: 371 (M+H). Calc'd for C₁₇H₁₈N₆O₂S: 370.12.

EXAMPLE 192

[1340]

[1341]1-{6-[2-Aminoethyl]pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1342] To a mixture of1-{6-[2-(phthalimidyl)ethyl]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea(75 mg, 0.16 mmol, Example 88) and EtOH (10 mL) was added hydrazinehydrate (0.1 mL, 0.18 mmol). The mixture was heated at reflux for 2 hthen cooled to RT. The residue was dissolved in 3:1 CHCl₃/IpOH, washedwith saturated NaHCO₃, dried (MgSO₄) and concentrated in vacuo to affordthe title compound as a yellow solid. MS m/z: 341.0 (M+H). Calc'd forC₁₆H₁₆N₆OS: 340.11.

EXAMPLE 193

[1343]

[1344]1-{6-[2-(N,N-Dimethylamino)ethyl]pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1345] To a solution of1-{6-[2-aminoethyl]pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea (20mg, 0.06 mmol, Example 192) and CH₂Cl₂ (5 mL) was added paraformaldehyde(20 mg) and NaBH(OAc)₃ (30 mg, 0.14 mmol). The mixture was stirred at RTfor 2.5 h. Extracted with 3:1 CHCl₃/IpOH and washed with brine, dried(MgSO₄) and concentrated in vacuo to afford the desired compound as ayellow solid. MS m/z: 369.1 (M+H). Calc'd for C₁₈H₂₀N₆OS: 368.14.

EXAMPLE 194

[1346]

[1347]1-[2-(2-Ethoxypyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea

[1348] To a mixture of1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea(100 mg, 0.23 mmol, Example 90) and EtOH (50 mL) was added a 21 wt %NaOEt/EtOH solution (0.4 mL, 1.2 mmol) and DMF (2 mL). The mixture washeated to reflux for 15 h then additional 21 wt % NaOEt/EtOH solution(10 mL) were added. After 2.5 h, the reaction was complete as judged byLC/MS. The reaction mixture was concentrated in vacuo then diluted withEtOAc and the solid was filtered off. The filtrate was concentrated invacuo to afford an orange slushy oil which was purified by silica flashchromatography (5-10% MeOH/CH₂Cl₂) to afford the title compound as ayellow solid. MS m/z: 441.1 (M+H). Calc'd for C₂₁H₂₄N₆O₃S: 440.16.

EXAMPLE 195

[1349]

[1350] 1-[2-(2-Methoxypyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmthyl-pyridin-2-yl)urea

[1351] To a mixture of1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-morpholin-4-ylmethyl-pyridin-2-yl)urea(100 mg, 0.23 mmol, Example 90) and MeOH (50 mL) was added solid NaOMe(1.6 g, 29.6 mmol) and DMF (20 mL). The reaction mixture was heated to130° C. After 2 h, the reaction mixture was cooled to RT and filtered.The filtrate was concentrated in vacuo and diluted with EtOAc andfiltered to remove the solid. The filtrate was concentrated in vacuo toafford an orange oil which was purified by silica flash chromatography(5% MeOH/CH₂Cl₂) to afford the title compound as a white solid. MS m/z:427.2 (M+H). Calc'd for C₂₀H₂₂N₆O₃S: 426.15.

EXAMPLE 196

[1352]

[1353]1-[2-(2-Ethoxypyridin-4-yl)thiazol-4-yl]-3-(6-ethyl-pyridin-2-yl)urea

[1354] To a 10 mL round bottom flask containing1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-ethylpyridin-2-yl)urea (40mg, 0.11 mmol) (prepared similar to that described for Example 95) wascharged a 21 wt % NaOEt/EtOH solution (5 mL). The reaction mixture washeated to reflux. After 2 h, the reaction mixture was cooled to RT anddiluted with H₂O then concentrated in vacuo. The solid residue waswashed with CH₂Cl₂ and EtOAc then the solid was diluted with MeOH andconcentrated in vacuo. The residue was diluted with EtOAc; washed withsaturated NH₄Cl and H₂O, dried (MgSO₄) and concentrated in vacuo toafford the title compound as a light-orange solid. MS m/z: 370.2 (M+H).Calc'd for C₁₈H₁₉N₅O₂S: 369.13.

EXAMPLE 197

[1355]

[1356]1-[2-(6-Methoxypyridin-3-yl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1357] To a solution of the 3-(4-methoxy-3-pyridyl)thiazole carboxylicacid (200 mg, 0.85 mmol) and dry toluene (20 mL) was added (PhO)₂PON₃(0.2 mL, 0.94 mmol) and TEA (0.13 mL, 0.94 mmol). The mixture was heatedto 85° C. for five min then 2-amino-6-methylpiperdinylpyridine (0.16 g,0.85 mmol) in CH₃CN (3 mL) was added. The reaction was heated at refluxfor 15 h then concentrated in vacuo and purified by silica flashchromatography (1% to 5% MeOH/CH₂Cl₂) to give the title compound as anorange oil. Diluted with MeOH (5 mL) and added one equivalent of 1M HClin Et₂O. Concentrated in vacuo to afford the HCl salt as an orangesolid. MS m/z: 424.9 (M+H). Calc'd for C₂₁H₂₄N₆O₂S: 424.17.

EXAMPLE 198

[1358]

[1359]1-(2-Bromothiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1360] To a stirred suspension of 2-bromothiazole-4-carboxylic acid(5.13 g, 2 mmol) in anhydrous CH₃CN (40 ml) at RT, under N₂, TEA (3.80ml, 27 mmol) and (PhO)₂PON₃ (5.90 ml, 27 mmol) were added. The resultingsolution was heated to 85° C. Upon reaching 85° C., a solution of6-(piperidylmethyl)-2-pyridylamine (4.74 g, 25 mmol) in anhydrous CH₃CN(60 ml) was added. The reaction was maintained at this temperature for2.25 h. After cooling to RT the mixture was diluted with CH₂Cl₂ (50 ml)then washed with a saturated solution of NH₄Cl(aq) (40 ml). The organiclayer was separated, dried over MgSO₄, filtered and concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel (3:1/2:1/1:1, EtOAc:acetone) to yield the title compound as apale yellow solid. MS m/z: 396 (M+H), 398 (M+3). Calc'd forC₁₅H₁₈BrN₅OS: 395.04.

EXAMPLE 199

[1361]

[1362]1-[2-(4-Methoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1363] A stirred suspension ofN-(2-bromo(1,3-thiazol-4-yl)){[6-(piperidylmethyl)(2-pyridyl)]amino}carboxamide (2.23 g, 5.64 mmol),4-methoxyphenylboronic acid (0.94 g, 6.21 mmol), PdCl₂(dppf)₂ (0.46 g,0.56 mmol) and Na₂CO₃ (2.10 g, 17.0 mmol) in ethylene glycol dimethylether (25 ml) and H₂O (8 ml) was heated at reflux for 12 h. Aftercooling to RT the mixture was filtered through Celite®. The filtrate wasconcentrated under reduced pressure. The crude product was purified byflash chromatography on silica gel (3:1, EtOAc:acetone) to yield thetitle compound as a pale yellow amorphous solid. MS m/z: 424 (M+H).Calc'd for C₂₂H₂₅N₅O₂S: 423.17.

[1364] The following compounds were prepared from the correspondingboronic acids in a manner similar to Example 199:

EXAMPLE 200

[1365]

[1366]1-(2-Benzo[1,3]dioxol-5-yl-thiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea

[1367] MS m/z: 438 (M+H). Calc'd for C₂₂H₂₃N₅O₃S: 437.15.

EXAMPLE 201

[1368]

[1369]1-[2-(3,4-Dimethoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1370] MS m/z: 454 (M+H). Calc'd for C₂₃H₂₇N₅O₃S: 453.18.

EXAMPLE 202

[1371]

[1372]1-[2-(4-Fluorophenyl)thiazol-4-yl]-3-(6-piperidin-1ylmethyl-pyridin-2-yl)urea

[1373] EI-MS m/z 412 (M+H). Calc'd for C₂₁H₂₂FN5OS: 411.15.

EXAMPLE 203

[1374]

[1375]1-[2-(3-Ethoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1376] EI-MS m/z 438 (M+H). Calc'd for C₂₃H₂₇N₅O₂S: 437.19.

EXAMPLE 204

[1377]

[1378] 1-[2-(3-Aminophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmthyl-pyridin-2-yl)urea

[1379] EI-MS m/z 409 (M+H). Calc'd for C₂₁H₂₄N₆OS: 408.17.

EXAMPLE 205

[1380]

[1381]1-[2-(4-Trifluoromethylophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1382] EI-MS m/z 462 (M+H). Calc'd for C₂₂H₂₂F₃N₅OS: 461.15.

EXAMPLE 206

[1383]

[1384]1-[2-(3-Trifluoromethylophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1385] EI-MS m/z 462 (M+H)⁺. Calc'd for Calc'd for C₂₂H₂₂F₃N₅OS: 461.15.

EXAMPLE 207

[1386]

[1387]1-[2-(3-Fluorophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1388] EI-MS m/z 412 (M+H). Calc'd for Calc'd for C₂₁H₂₂FN₅OS: 411.15.

EXAMPLE 208

[1389]

[1390]1-[2-(4-Dimethylaminophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1391] EI-MS m/z 437 (M+H). Calc'd for C₂₃H₂₈N₆OS: 436.20.

EXAMPLE 209

[1392]

[1393]1-[2-phenylthiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1394] EI-MS m/z 394 (M+H). Calc'd for C₂₁H₂₃N₅OS: 393.16.

EXAMPLE 210

[1395]

[1396]1-[2-(4-Aminophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1397] EI-MS m/z 409 (M+H). Calc'd for C₂₁H₂₄N₆OS: 408.17.

EXAMPLE 211

[1398]

[1399]1-[2-(3,5-Dichlorophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1400] EI-MS m/z 462 (M+H). Calc'd for C₂₁H₂₁Cl₂N₅OS: 461.08.

EXAMPLE 212

[1401]

[1402]1-[2-(2,4-Difluorophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1403] EI-MS m/z 430 (M+U). Calc'd for C₂₁H₂₁F₂N₅OS: 429.14.

EXAMPLE 213

[1404]

[1405]1-[2-(3,4-Dichlorophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1406] EI-MS m/z 462 (M+H). Calc'd for C₂₁H₂₁Cl₂N₅OS: 461.08.

EXAMPLE 214

[1407]

[1408]1-[2-(1H-Indol-5-yl)-thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea

[1409] EI-MS m/z 433 (M+H). Calc'd for C₂₃H₂₄N₆OS: 432.17.

EXAMPLE 215

[1410]

[1411]1-[2-(4-Methylthiophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1412] EI-MS m/z 440 (M+H). Calc'd for C₂₂H₂₅N₅OS₂: 439.15.

EXAMPLE 216

[1413]

[1414]1-[2-(4-Cyanophenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1415] EI-MS m/z 419 (M+H). Calc'd for C₂₂H₂₂N₆OS: 418.16

EXAMPLE 217

[1416]

[1417]1-[2-(3-Methoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1418] To a stirred solution of2-(3-methoxyphenyl)-1,3-thiazole-4-carboxylic acid (0.17 g, 0.72 mmol)in toluene (10 mL) at RT and under N₂ was added TEA (0.2 mL). After 5min, (PhO)₂PON₃ (0.2 5 mL) was added and the reaction mixture was heatedat 85° C. for 20 min followed by the addition of6-(piperidylmethyl)-2-pyridylamine (0.21 g, 1.1 mmol). The resultingmixture was heated at reflux for 4 h using a Dean-Stark trap. Themixture was cooled to RT, concentrated by rotary evaporation andpurified on silica gel (5:95 MeOH/CH₂Cl₂). The yellow solid obtained wasdissolved in EtOAc (15mL) and washed with a saturated solution of NH₄Cl(aq). The organic phase was separated, dried over MgSO₄, filtered andconcentrated by rotary evaporation. The product was recrystallized fromhexanes to afford the title compound as a white solid. EI-MS m/z 424(M+H). Calc'd for C₂₂H₂₅N₅O₂S: 423.17.

EXAMPLE 218

[1419]

[1420] 1-[2-(2-Methoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmthyl-pyridin-2-yl)urea

[1421] To a stirred solution of2-(2-methoxyphenyl)-1,3-thiazole-4-carboxylic acid (0.22 g, 0.94 mmol)in toluene (10 mL) at RT and under N₂ was added TEA (0.3 mL). After 5min, (PhO)₂PON₃ (0.32 mL) was added and the reaction mixture was heatedat 85° C. for 20 min followed by the addition of6-(piperidylmethyl)-2-pyridylamine (0.27 g, 1.41 mmol). The resultingmixture was heated at reflux for 4 h using a Dean-Stark trap. Themixture was cooled to RT, concentrated by rotary evaporation andpurified on silica gel (5:95 MeOH/CH₂Cl₂). The yellow solid obtained wasdissolved in EtOAc (15 mL) and washed with saturated NH₄Cl (10 mL). Theorganic phase was separated, dried over MgSO₄, filtered and concentratedby rotary evaporation to afford the title compound as a pale-yellowsolid. EI-MS m/z 424 (M+H). Calc'd for C₂₂H₂₅N₅O₂S: 423.17.

EXAMPLE 219

[1422]

[1423]1-[2-(3-Hydroxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1424] A mixture of1-[2-(3-methoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea(Example 218) and beryllium chloride (5.0 eq) in dry toluene (0.2 M) and4A molecular sieves was heated at reflux for 10 h. The starting materialwas not totally soluble in toluene. The mixture was brought to RT,diluted with EtOAc and washed with saturated NH₄Cl. The organic phasewas separated, dried over MgSO₄, filtered, concentrated by rotaryevaporation and purified by prep HPLC (Column Phenomenex type Prodigy 50ODS3 100A size 250×21.20 mm 5 u, Gradient 10% to 90% CH₃CN:H₂Ocontaining 1% TFA over 20 min, Detector 254 nm, 4 nm Band) to afford thetitle compound as an off white solid. EI-MS m/z 410 (M+H). Calc'd forC₂₁H₂₃N₅O₂S: 409.16.

EXAMPLE 220

[1425]

[1426]1-[2-(4-Methoxyphenoxymethyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1427] To a stirred solution of2-[(4-methoxyphenoxy)-methyl]-1,3-thiazole-4-carboxylic acid (0.10 g,0.38 mmol) and TEA (0.06 mL, 0.46 mmol) in dry toluene (15 mL) and 4A°molecular sieves was added (PhO)₂PON₃ (0.10 mL, 0.46 mmol) The resultingmixture was heated at 85° C. for 25 min followed by the addition of6-(piperidyl-methyl)-2-pyridylamine (0.09 g, 0.46 mmol). The resultingmixture was heated to reflux for 15 h, cooled to RT, filtered,concentrated by rotary evaporation and purified on silica gel (5:95MeOH/CH₂Cl₂) to afford the title compound as a yellow oil. EI-MS m/z 454(M+H). Calc'd for C₂₃H₂₇N₅O₃S: 453.18.

EXAMPLE 221

[1428]

[1429]1-{6-[(2-Diethylamino-1-methylethylamino)methyl]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1430] Step A

[1431] To a stirred solution ofN-[(6-amino(2-pyridyl))methyl]-N-[2-(diethylamino)-isopropyl](tert-butoxy)-carboxamide(30 mg, 0.09 mmol) in toluene (5 mL) was added2-aza-2-diazo-1-(2-(4-pyridyl) (1,3-thiazol-4-yl))ethen-1-one (0.02 g,0.09 mmol). The resulting green solution was heated to reflux in aDean-Stark trap for 1.5 h until the starting materials were consumed.The mixture was brought to RT, concentrated by rotary evaporation andthe residue obtained was partitioned between H₂O (10 mL) and CHCl₃ (10ml). The organic phase was separated and the aqueous phase was extracted(3×10 ml) with CHCl₃. The organic layers were combined, dried overMgSO₄, filtered, concentrated by rotary evaporation and purified by prepTLC (10:90 MeOH/CH₂Cl₂) to afford tert butyl(2-dimethylamino-1-methyl-ethyl)-(6-[3-(2-pyridin-4-yl-thiazol-4-yl)ureido]pyridin-2-yl}carbamateas a white solid. EI-MS m/z 540 (M+H). Calc'd for C₂₇H₃₇N₇O₃S: 539.27.

[1432] Step B

[1433] To a stirred solution ofN-[2-diethylamino)-ethyl](tert-butoxy)-N-[(6-{[N-(2-(4-pyridyl)(1,3-thiazol-4-yl))carbamoyl]amino}(2-pyridyl))methyl]-carboxamide (4mg, 0.007 mmol) in dry CH₂Cl₂ (1 mL) was added TFA (1 mL). The resultingsolution was stirred at RT and under N₂ atmosphere for 2 h, concentratedby rotary evaporation and the residue was diluted with EtOAc (5 mL) andwashed with a saturated solution of NaHCO₃ (aq) (15 mL). The organicphase was separated, dried over MgSO₄, filtered, concentrated by rotaryevaporation and purified by prep TLC (1:1 MeOH/CH₂Cl₂) to yield1-{6-[(2-diethylamino-1-methylethylamino)methyl]-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea.EI-MS m/z 540 (M+H). Calc'd for C₂₂H₂₉N₇OS: 439.22.

EXAMPLE 222

[1434]

[1435]4-{4-[3-(6-Piperidin-1-ylmethyl-pyridin-2-yl)-ureido]thiazol-2-yl}-benzenesulfonamide

[1436] To a stirred solution of ethyl2-(4-sulfamoyl-phenyl)-1,3-thiazole-4-carboxylic acid (90 mg, 0.32 mmol)in dry TFA (3 mL) and 4A molecular sieves at RT and under N₂ was addedTEA (0.1 mL). After 5 min, (PhO)₂PON₃ (0.11 mL) and6-(piperidylmethyl)-2-pyridylamine (0.10 g, 0.51 mmol) were added andthe reaction mixture was heated to reflux for 4 h and then cooled to RT.The mixture was washed with 10% HCl (aq) and extracted with EtOAc (3×10mL). The aqueous layer was brought to a pH 8.0 and extracted with CH₂Cl₂(3×20 mL). The extracts were combined, dried over MgSO₄, concentrated byrotary evaporation and purified on silica gel (2:1 hexanes/EtOAc and 1:1MeOH/CH₂Cl₂) to afford the title compound as a pale yellow solid. EI-MSm/z 473 (M+H). Calc'd for C₂₁H₂₄N₆O₃S₂: 472.14.

EXAMPL 223

[1437]

[1438] Ethyl2-[3-[2-(pyridin-4-yl)-thiazol-4-yl]ureido]-thiazole-4-carboxylate2-(4-Pyridinyl)-4-thiazolcarbonylazide (420 mg, 1.8 mmol) in dry toluene(20 mL) was heated to 85° C. under N₂ and maintained at this temperaturefor 5 min. A solution of 2-amino-4-thiazolcarboxylic acid ethyl ester(350 mg, 2.0 mmol) was added and the resulting mixture was heated at 85°C. for 15 h. After cooling to RT, a precipitate formed and was filteredto give the desired compound as a yellow solid. MS m/z: 376.0 (M+H).Calc'd for C₁₅H₁₃N₅O₃S₂: 375.05.

EXAMPLE 224

[1439]

[1440]1-(4-Cyclohexylthiazol-2-yl)-3-[2-(pyridin-4-yl)-thiazol-4-yl]urea

[1441] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (200 mg, 0.87 mmol) in drytoluene (10 mL) was heated to 85° C. under N₂ and maintained at thistemperature for 5 min. A solution of 2amino-4-cyclohexylthiazole (158mg, 0.87 mmol) was added and the resulting mixture was heated at 85° C.for 15 h. After cooling to RT, a precipitate formed and was filtered togive the desired compound as a yellow solid. MS m/z: 386.0 (M+H). Calc'dfor C₁₈H₁₉N₅OS₂: 385.10.

EXAMPL 225

[1442]

[1443] 1-(Pyridin-3-ylmethyl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1444] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (100 mg, 0.43 mmol) in drytoluene (3 mL) was heated to 105° C. under N₂ and maintained at thistemperature for 5 min. A solution of 3-(aminomethyl)pyridine (47 mg,0.43 mmol) in dry toluene (1 mL) was added dropwise via syringe and theresulting mixture heated at 105° C. for 2 h. After cooling to RT,solvent was removed under vacuum and the product was purified by silicagel chromatograpy eluting with MeOH/CH₂Cl₂ (10%) to give the desiredcompound as a light yellow solid. MS m/z: 312.1 (M+H). Calc'd forC₁₅H₁₃N₅OS: 311.08.

EXAMPLE 226

[1445]

[1446] 1-(Pyridin-2-ylmethyl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1447] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (100 mg, 0.43 mmol) in drytoluene (3 mL) was heated to 105° C. under N₂ and maintained at thistemperature for 5 min. A solution of 2-(aminomethyl)pyridine (47 mg,0.43 mmol) in dry toluene (1 mL) was then added dropwise via syringe andthe resulting mixture heated at 105° C. for 3 h. After cooling to RT,solvent was removed under vacuum and the product was purified by silicagel chromatograpy eluting with MeOH/CH₂Cl₂ (10%) to give a light yellowsolid. MS m/z: 312.1 (M+H). Calc'd for C₁₅H₁₃N₅OS: 311.08.

EXAMPLE 227

[1448]

[1449]1-[6-(Piperidin-1-ylmethyl)pyridin-2-yl]-3-(3-pyridin-3-yl-phenyl)urea

[1450] To a stirred solution of phosgene (0.35 mL, 0.65 mmol, 20% intoluene) in dry THF (5 mL) was added 3-(3-pyrid-1-yl)-1-aminobenzene (85mg, 0.5 mmol) dropwise via the addition funnel. After stirring for 10min, isopropylethylamine (0.26 mL, 2.0 mmol) was added. The resultingmixture was stirred at RT under N₂ for 30 min.2-Amino-6-piperidinylmethylpyridine (96 mg, 0.5 mmol) in dry THF (5 mL)was added dropwise into the reaction mixture via the addition funnel.The resulting mixture was stirred at RT for 15 h. Solvent was removed togive a dark brown liquid which was purified by chromatography on silicagel. Elution with CH₂Cl₂:MeOH mixture (95:5) gave the final compound asa pale yellow solid. MS m/z: 387.9 (M+). Calc'd. for C₂₃H₂₅N₅O—387.49.

EXAMPLE 228

[1451]

[1452] 1-(3-Hydroxy-pyridin-2-yl)-3-(2-pyridin-3-yl-thiazol-4-yl)-urea

[1453] TEA (0.27 mL, 1.94 mmol) was added to a solution of2-(pyridin-3-yl)thiazole-4-carboxylic acid (200 mg, 0.97 mmol) and 4Amolecular sieves in THP (25 mL) under N₂ at RT. (PhO)₂PON₃ (0.33 mL,1.55 mmol) followed by 2-amino-6-hydroxypyridine (268 mg, 2.43 mmol) wasadded and the resulting mixture heated at reflux for 12 h. After coolingto RT, the heterogeneous mixture was decanted to remove the molecularsieves. The precipitate was collected, rinsing with EtOAc to give awhite solid. MS m/z: 313.0 (M+H). Calc'd for C₁₄H₁₁N₅O₂S—313.34.

EXAMPLE 229

[1454]

[1455] 1-(³-Amino-pyridin-2-yl)-3-(2-pyridin-3-yl-thiazol-4-yl)-urea

[1456] TEA (0.27 mL, 1.94 mmol) was added to a solution of2-(pyridin-³-yl)thiazole-4-carboxylic acid (200 mg, 0.97 mmol) and 4Amolecular sieves in THF (25 mL) under N₂ at RT. (PhO)₂PON₃ (0.33 mL,1.55 mmol) followed by 2-amino-3aminomethylpyridine (265 mg, 2.43 mmol)was added and the resulting mixture was heated at reflux for 12 h. Aftercooling to RT, the heterogeneous mixture was decanted to remove themolecular sieves. The precipitate was collected and discarded. Thefiltrate was purified by chromatography on silica gel (CH₂Cl₂/MeOH,95:5) to give a white solid. MS m/z: 313.8 (M+H). Calc'd forC₁₄H₁₂N₆OS—312.36.

EXAMPLE 230

[1457]

[1458] 1-(3-Hydroxy-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1459] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (200 mg, 0.86 mmol) and2-amino-3-hydroxymethylpyridine (95 mg, 0.86 mmol) in dry toluene (10mL) were heated at 100° C. for 12 h to give a pale yellow solid whichwas recrystallized from CHCl₃/MeOH (99:5) to give a pale yellow solid.MS m/z: 314.0 (M+H). Calc'd for C₁₄H₁₁N₅O₂S—313.34.

EXAMPLE 231

[1460]

[1461] 1-(3-Amino-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1462] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (200 mg, 0.86 mmol) and2-amino-3-aminomethylpyridine (94 mg, 0.86 mmol) in dry toluene (10 mL)were heated at 100° C. for 12 h to give a pale yellow solid which wasrecrystallized from CHCl₃/MeOH (99:5) to give a pale yellow solid. MSm/z: 313.0 (M+H). Calc'd for C₁₄H₁₂N₆OS—312.36.

EXAMPLE 232

[1463]

[1464](1-Diethylaminomethyl-2-methyl-propyl)-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamicacid tert-butyl ester

[1465] To a stirred solution ofN-[(6-amino-(2-pyridyl))methyl]-N-{1-[(diethylamino)methyl]-2-methylpropyl}-(tert-butoxy)carboxamide(6 mg, 0.016 mmol) in toluene (5 mL) was added6-(piperidylmethyl)-2-pyridylamine (0.004 g, 0.016 mmol). The resultinggreen solution was heated at reflux in a Dean-Stark trap for 1.5 h untilthe starting materials were consumed. The mixture was brought to RT,concentrated by rotary evaporation and the residue obtained waspartitioned between H₂O (10 mL) and CHCl₃ (35 mL). The organic phase wasseparated and the aqueous phase was extracted with CHCl₃ (3×10 mL). Theorganic layers were combined, dried over MgSO₄, filtered, concentratedby rotary evaporation and purified by prep TLC (5:95 MeOH/CH₂Cl₂) toafford(1-diethylaminomethyl-2-methyl-propyl)-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamicacid tert-butyl ester as an off-white solid. EI-MS m/z 568 (M+H). Calc'dfor C₂₉H₄₁N₇O₃S: 567.30.

EXAMPLE 233

[1466]

[1467]1-(3-Piperidin-1-ylmethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1468] MS m/z: 395 (M+H). Calc'd MS C₂₀H₂₂N₆OS—394.49.

EXAMPLE 234

[1469]

[1470]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(2,2,6,6-tetramethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea

[1471] 2-(4-Pyridinyl)-4-thiazolcarbonylazide (35 mg, 0.15 mmol) in drytoluene (10 mL) was heated to 80° C. under N₂ and maintained at thistemperature for 10 min. A solution of6-(2,2,6,6-tetramethyl-piperidin-1-ylmethyl)-pyridin-2-ylamine (30 mg,0.12 mmol) in dry toluene (2 mL) was added dropwise via syringe and theresulting mixture heated at 85° C. for 3 h. After cooling to RT, thecrude mixture was purified by chromatography on silica gel (MeOH/CHCl₃,3:97) to give a pale yellow solid. MS m/z: 449.3 (M−H). Calc'd forC₂₄H₃₀N₆OS—450.60.

EXAMPLE 235

[1472]

[1473]1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea

[1474] In a manner similar to that described in Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide (100 mg, 0.43 mmol) in drytoluene (10 mL) was heated with6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-ylamine (106 mg, 0.52 mmol)to give an off-white solid. MS m/z: 408.3 (M+H). Calc'd forC₂₂H₂₅N₅OS—407.53.

EXAMPLE 236

[1475]

[1476]1-[4-(Piperidine-1-carbonyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1477] In a manner similar to that described in Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide (100 mg, 0.43 mmol) was heatedwith (2-amino-pyridin-4-yl)-piperidin-1-yl-methanone (88 mg, 0.43 mmol)in dry toluene (10 mL) to give a white solid. MS m/z: 409.3 (M+H).Calc'd. for C₂₀H₂₀N₆O₂S—408.14.

EXAMPLE 237

[1478]

[1479]1-(2-Chloro-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea

[1480] In a manner similar to that described in Example 234,2-chloro-4-thiazolcarbonylazide (74 mg, 0.39 mmol) was heated with4-piperidin-1-ylmethyl-pyridin-2-ylamine (80 mg, 0.39 mmol) in drytoluene (10 mL) to give a white solid. MS m/z: 366.2 (M+H). Calc'd. forC₁₅H₁₆ClN₅O₂S—365.07.

EXAMPLE 238

[1481]

[1482]N,N-Diethyl-2-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-isonicotinamide

[1483] In a manner similar to that described in Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide (95 mg, 0.41 mmol) was heatedwith 2-amino-N,N-diethyl-isonicotinamide (80 mg, 0.41 mmol) in drytoluene (10 mL) to give a white solid. MS m/z: 397.2 (M+H). Calcld. forC₁₉H₂₀N₆O₂S—396.14.

EXAMPLE 239

[1484]

[1485] N,N-Diethyl-2-[3-(2-phenyl-thiazol-4-yl)-ureido]-isonicotinamide

[1486] In a manner similar to that described in Example 234,2-phenyl-4-thiazolcarbonylazide (83 mg, 0.36 mmol) was heated with2-amino-N,N-diethyl-isonicotinamide (70 mg, 0.36 mmol) in dry toluene(10 mL) to give a white solid. MS m/z: 396.3 (M+H). Calc'd. forC₁₉H₂₀N₆O₂S—395.14.

EXAMPLE 240

[1487]

[1488] 2-[3-(2-Bromo-thiazol-4-yl)-ureido]-N,N-diethy-lisonicotinamide

[1489] In a manner similar to that described in Example 234,2-bromo-4-thiazolcarbonylazide (85 mg, 0.36 mmol) was heated with2-amino-N,N-diethyl-isonicotinamide (70 mg, 0.36 mmol) in dry toluene(10 mL) to give a white solid. MS m/z: 398.1 (M+H). Calc'd. forC₁₄H₁₆BrN₅O₂S—397.02.

EXAMPLE 241

[1490]

[1491] 2-[3-(2-Chloro-thiazol-4-yl)-ureido]-N,N-diethyl-isonicotinamide

[1492] In a manner similar to that described in Example 234,2-chloro-4-thiazolcarbonylazide (50 mg, 0.26 mmol) was heated with2-amino-N,N-diethyl-isonicotinamide (50 mg, 0.26 mmol) in dry toluene(10 mL) to give a white solid. MS m/z: 354.2 (M+H). Calc'd. forC₁₄H₁₆ClN₅O₂S—353.07.

EXAMPLE 242

[1493]

[1494]1-(4-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1495] In a manner similar to that described in Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide (78 mg, 0.34 mmol) was heatedwith 4-diethylaminomethyl-pyridin-2-ylamine (60 mg, 0.34 mmol) in drytoluene (10 mL) to give a white solid. MS m/z: 383.2 (M+H). Calc'd. forC₁₉H₂₂N₆OS—382.16.

EXAMPLE 243

[1496]

[1497]1-(4-Diethylaminomethyl-pyridin-2-yl)-3-(2-phenyl-thiazol-4-yl)-urea

[1498] In a manner similar to that described in Example 234,2-phenyl-4-thiazolcarbonylazide (77 mg, 0.34 mmol) was heated with4-diethylaminomethyl-pyridin-2-ylamine (60 mg, 0.34 mmol) in dry toluene(10 mL) to give a white solid. MS m/z: 382.1 (M+H). Calc'd. forC₁₉H₂₂N₆OS—381.16.

EXAMPLE 244

[1499]

[1500]1-(2-Bromo-thiazol-4-yl)-3-(4-diethylaminomethyl-pyridin-2-yl)-urea

[1501] In a manner similar to that described in Example 234,2-bromo-4-thiazolcarbonylazide (85 mg, 0.36 mmol) was heated with4-diethylaminomethyl-pyridin-2-ylamine (65 mg, 0.36 mmol) in dry toluene(10 mL) to give a white solid. MS m/z: 384.1 (M+H). Calc'd. forC₁₄H₁₈BrN₅OS—383.04.

EXAMPLE 245

[1502]

[1503]1-[6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1504] In a manner similar to that described in Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide (132 mg, 0.57 mmol) was heatedwith 6-(2,6-dimethyl-piperidin-1-ylmethyl)-pyridin-2-ylamine (125 mg,0.57 mmol) in dry toluene (10 mL) to give a yellow solid. MS m/z: 423.3(M+H). Calc'd. for C₂₂H₂₆N₆OS—422.19.

EXAMPLE 247

[1505]

[1506]1-[6-(1-Piperidin-1-yl-ethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1507] In a manner similar to that described in Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide (180 mg, 0.78 mmol) was heatedwith 6-(1-piperidin-1-yl-ethyl)-pyridin-2-ylamine (160 mg, 0.78 mmol) indry toluene (10 mL) to give a yellow solid. MS m/z: 409.2 (M+H). Calc'd.for C₂₁H₂₄N₆OS—408.17.

EXAMPLE 248

[1508]

[1509]2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester

[1510] In a manner similar to that described in Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide (45 mg, 0.196 mmol) was heatedwith 2-[(6-amino-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert-butyl ester (60 mg, 0.196 mmol) in dry toluene (10 mL) to give ayellow solid. MS m/z: 510.4 (M+H). Calc'd. for C₂₅H₃₁N₇O₃S—509.2.

EXAMPLE 249

[1511]

[1512]1-{6-[(Piperidin-2-ylmethyl)-amino]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1513]2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (52 mg, 0.102 mmol) in MeOH (10 mL) was treatedwith TFA (0.1 mL, 1.3 mmol). The resulting mixture was heated at 50° C.for 24 h. The reaction mixture was cooled to RT and neutralized to pHbetween 8-9. Solvent was removed. The residue was partitioned betweenH₂O and CHCl₃. The organic layer was washed with H₂O, brine, dried overMgSO₄, and concentrated to give a yellow solid. MS m/z: 410.2 (M+H).Calc'd. for C₂₀H₂₃N₇OS—409.17.

EXAMPLE 250

[1514]

[1515](S)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1516]1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea(50 mg, 0.12 mmol, Example 78) was separated by chiral HPLC (ChiraltechChiralcel OJ 50×4.6 mm i.d.) using hexane/EtOH/DEA (90:10:0.2) to give awhite solid. MS m/z: 409.3 (M+H). Calc'd for C₂₁H₂₄N₆OS—408.52.

EXAMPLE 251

[1517]

[1518](R)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1519]1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea(50 mg, 0.12 mmol, Example 78) was separated by chiral HPLC (ChiraltechChiralcel OJ 50×4.6 mm i.d.) using hexane/EtOH/DEA (90:10:0.2) to give awhite solid. MS m/z: 409.3 (M+H). Calc'd for C₂₁H₂₄N₆OS—408.52.

EXAMPLE 252

[1520]

[1521]5-{4-[3-(6-Piperidin-ylmethylpyridin-2-yl)-ureido]thiazol-2-yl}-indole-1-carboxylicacid tert-butyl ester

[1522] To a solution of 5-(4-carboxy-thiazol-2-yl)-indole-1-carboxylicacid tert-butyl ester (2.65 g, 7.69 mmol), molecular sieves, and 100 mLof dry toluene was added TEA (1.6 mL, 11.5 mmol). The resulting solutionwas stirred for 20 min then DPPA (2.5 mL, 11.6 mmol) was added and theresulting solution was stirred at 80° C. for 40 min.6-Piperdin-1-ylmethyl-pyridin-2-ylamine (1.64 g, 8.6 mmol) and pyridine(1.0 mL, 12.4 mmol) were added and the mixture was stirred at 80° C. foranother 14 h. The molecular sieves were filtered off and washed withCH₂Cl₂ and MeOH. The filtrate was concentrated in vacuo and theresulting residue was purified by flash chromatography on silica gelusing 3% MeOH/CH₂Cl₂ to give a brown solid. MS m/z: 533 (M+1). Calc'dfor C₂₈H₃₂N₆O₃S—532.66.

EXAMPLE 253

[1523]

[1524](1-{4-[3-(6-Piperidin-1-ylmethyl-pyridin-2-yl)-ureido]-thiazol-2-yl}-piperidin-3-ylmethyl)-carbamicacid benzyl ester

[1525] To a stirred solution of2-[3-(benzyloxy-carbonylamino-methyl)-piperidin-1-yl]-thiazole-4-carboxylicacid (351 mg, 0.93 mmol) in anhydrous toluene (15 mL), under N₂, at RT,over 4A activated molecular sieves, TEA (0.16 mL, 1.12 mmol) was added.After 7 min, DPPA (0.24 mL, 1.12 mmol) was added and the solution washeated to 85° C. for 20 min. Neat6-piperidin-1-ylmethyl-pyridin-2-ylamine (179 mg, 0.93 mmol) was addedand the reaction was maintained at 85° C. for an additional 2.5 h. Aftercooling to RT the solution was filtered through a Celite® pad that waswashed successively with CH₂Cl₂ (4×5 mL). The filtrate was evaporated invacuo and the residue purified by flash chromatography on silica gel(97:3, CHCl₃:MeOH) to yield the title compound as a red/orange oil. MSm/z: 564.4 (M+H). Calc'd. for C₂₉H₃₇N₇O₃S—563.72.

EXAMPLE 254

[1526]

[1527]4-(2-{6-[3-(2-Bromo-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylicacid tert-butyl ester

[1528] To a stirred solution of 2-bromo-thiazole-4-carbonyl azide (194mg, 0.83 mmol) in anhydrous toluene (4 mL) under N₂, that had beenheated to 85° C. and held there for 5 min, a solution of4-[2-(6-amino-pyridin-2-yloxy)-ethyl]-piperidine-1-carboxylic acidtert-butyl ester (268 mg, 0.83 mmol) in anhydrous toluene (3 mL) wasadded over 5 min. After 3 h the reaction mixture was cooled to RT. Theprecipitate was filtered off to yield the title compound as a whiteamorphous solid. MS m/z: 526.1, 528.1 (M+H). Calc'd. forC₂₁H₂₈BrN₅O₄S—526.4.

[1529] The following Examples 255-263 were prepared from theirrespective amines and azides in a manner similar to example 254.

EXAMPLE 255

[1530]

[1531]4-(2-{6-[3-(2-Chloro-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylicacid tert-butyl ester

[1532] MS m/z: 482.3 (M+H). Calc'd. for C₂₁H₂₈ClN₅O₄S—482.00.

EXAMPLE 256

[1533]

[1534]3-{6-[3-(2-Bromo-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-azetidine-1-carboxylicacid tert-butyl ester

[1535] MS m/z: 484.1, 486.1 (M+H). Calc'd. for C₁₈H₂₂BrN₅O₄S—484.37.

EXAMPLE 257

[1536]

[1537]3-{6-[3-(2-Chloro-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-azetidine-1-carboxylicacid tert-butyl ester

[1538] MS m/z: 440.1 (M+H). Calc'd. for C₁₈H₂₂ClN₅O₄S—439.92.

EXAMPLE 258

[1539]

[1540]1-(2-Chloro-thiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea

[1541] MS m/z: 352.3 (M+H). Calc'd. for C₁₅H₁₈ClN₅OS—351.86.

EXAMPLE 259

[1542]

[1543]4-{6-[3-(2-Bromo-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-piperidine-1-carboxylicacid tert-butyl ester

[1544] MS m/z: 512.3, 514.3 (M+H). Calc'd. for C₂₀H₂₆BrN₅O₄S—512.42.

EXAMPLE 260

[1545]

[1546]4-{6-[3-(2-Chloro-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-piperidine-1-carboxylicacid tert-butyl ester

[1547] MS m/z: 468.1 (M+H). Calc'd. for C₂₀H₂₆ClN₅O₄S—467.97.

EXAMPLE 261

[1548]

[1549]1-(2-Bromo-thiazol-4-yl)-3-(6-diethylaminomethyl-pyridin-2-yl)-urea

[1550] MS m/z: 384.1, 386.1 (M+H). Calc'd. for C₁₄H₁₈BrN₅OS—384.30.

EXAMPLE 262

[1551]

[1552]1-(2-Chloro-thiazol-4-yl)-3-(6-diethylaminomethyl-pyridin-2-yl)-urea

[1553] MS m/z: 340.2 (M+H). Calc'd. for C₁₄H₁₈ClN₅OS—339.84.

EXAMPLE 263

[1554]

[1555]1-(2-Bromo-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea

[1556] To a stirred solution of4-(2-{6-[3-(2-bromo-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylicacid tert-butyl ester (285 mg, 0.54 mmol) in anhydrous CH₂Cl₂ (6 mL) atRT, under N₂, TFA (1.5 mL) was added. After 1.5 h the solvent wasevaporated in vacuo. The residue was carefully treated with a saturatedsolution of NaHCO₃ (aq) (10 mL), the precipitate was filtered off,washed with Et₂O (3×5 mL) and dried in a vacuum oven at 60° C. for 5 hto yield the title compound as a white amorphous solid. MS m/z: 426.2,428.2 (M+H). Calc'd. for C₁₆H₂₀BrN₅O₂S—426.33.

[1557] The following Examples 264-268 were prepared from theirrespective tert-butyl esters in a manner similar to example 263.

EXAMPLE 264

[1558]

[1559] 1-(2-Chloro-thiazol-4-yl)-3-[6-(2-pipridin-4-yl-ethoxy)-pyridin-2-yl]-urea

[1560] MS m/z: 382.3 (M+H). Calc'd. for C₁₆H₂₀ClN₅O₂S—381.88.

EXAMPLE 265

[1561]

[1562]1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-bromo-thiazol-4-yl)-urea

[1563] MS m/z: 384.0, 386.0 (M+H). Calc'd. for C₁₃H₁₄BrN₅O₂S—384.25.

EXAMPLE 266

[1564]

[1565]1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-chloro-thiazol-4-yl)-urea

[1566] MS m/z: 340.1 (M+H). Calc'd. for C₁₃H₁₄ClN₅O₂S—339.80.

EXAMPLE 267

[1567]

[1568]1-(2-Bromo-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea

[1569] MS m/z: 412.0, 414.0 (M+H). Calc'd. for C₁₅H₁₈BrN₅O₂S—412.31.

EXAMPLE 268

[1570]

[1571]1-(2-Chloro-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea

[1572] MS m/z: 368.2 (M+H). Calc'd. for C₁₅H₁₈ClN₅O₂S—367.85.

EXAMPLE 269

[1573]

[1574]1-(2-Cyclopropyl-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea

[1575] In a manner similar to that described in Example 2,2-cyclopropylthiazole-4-carbonylazide (97.0 mg, 0.5 mmol) and6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-ylamine (103.5 mg, 0.5mmol) were heated in toluene (20 mL) to give the product as a yellowoil. MS m/z: 374.2 (M+H). Calc'd. for C₁₈H₂₄N₅O₂S—374.2.

EXAMPLE 270

[1576]

[1577]3-(4-{3-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-ureido}-thiazol-2-yl)-benzenesulfonamide

[1578] In a manner similar to that described in Example 2,2-2-(3-sulfamoyl-phenyl)-thiazole-4-carbonylazide (224.0 mg, 0.725 mmol)and 6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-ylamine (150.0 mg,0.725 mmol) were heated in toluene (70 mL) to give the product as awhite solid. MS m/z: 489.2 (M+H). Calc'd. for C₂₁H₂₅N₆O₄S₂—489.2.

EXAMPLE 271

[1579]

[1580]1-[2-(2,4-Dimethoxyphenyl)thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)urea

[1581] The title compound was prepared by the method of Example 199.EI-MS m/z 454 (M+H). Calc'd for C₂₃H₂₇N₅O₃S: 453.18.

EXAMPLE 272

[1582]

[1583]1-(2-Cyclopropylethynyl-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea

[1584] In a manner similar to that described in Example 2,2-2-cyclopropylethynyl-thiazole-4-carbonylazide (41.4 mg, 0.190 mmol)and 6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-ylamine (47.2 mg,0.228 mmol) were heated in toluene (1 mL) to give the product as a paleyellow solid. MS m/z: 398.3 (M+H). Calc'd. for C₂₀H₂₄N₅O₂S—397.16.

EXAMPLE 273

[1585]

[1586] tert-Butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-pyrrolidine-1-carboxylate

[1587] In a manner similar to that described in Example 2,2-2-pyridin-4-yl-thiazole-4-carbonylazide (1.927 g, 8.334 mmol) andtert-butyl 3-(6-amino-pyridin-2-yloxymethyl)pyrrolidine-1-carboxylate(2.220 g, 7.577 mmol) were heated in toluene (60 mL) to give the productas a white solid. MS m/z: 497.0 (M+H). Calc'd. for C₂₄H₂₉N₆O₄S—497.2.

EXAMPLE 274

[1588]

[1589]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-3-ylmethoxy)-pyridin-2-yl]-urea

[1590] To a slurry of tert-butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-pyrrolidine-1-carboxylate(1.291 g, 2.603 mmol) in CH₂Cl₂ (25 mL) was added TFA (5 mL) under N₂.The reaction mixture was heated to reflux for 3 h, then cooled to rt.Saturated NaHCO₃ solution (40 mL) was added and the precipitate waswashed with EtOAc (3×40 mL) and H₂O (2×10 mL), filtered and dried underhigh vacuum to give a white solid. MS m/z: 397.0 (M+H). Calc'd. forC₁₉H₂₁N₆O₂S—397.1.

EXAMPLE 275

[1591]

[1592]1-(2-Cyclopropyl-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea

[1593] In a manner similar to that described in Example 2,2-cyclopropylthiazole-4-carbonylazide (133.0 mg, 0.686 mmol) andtert-butyl 4-[2-(6-amino-pyridin-2-yloxy)-ethyl]piperidine-1-carboxylate(220.0 mg, 0.686 mmol) were heated in toluene (20 mL) to give theBOC-protected product as a yellow oil. In a similar manner to Example274, tert-butyl4-(2-{6-[3-(2-cyclopropyl-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylate(7.6 mg, 0.016 mmol) was heated in CH₂Cl₂ (10 mL) in the presence of TFA(2 mL) to give the product as yellow oil. MS m/z: 388.3 (M+H). Calc'd.for C₁₉H₂₆N₅O₂S—388.2.

EXAMPLE 276

[1594]

[1595]Isopropyl-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-carbamicacid tert-butyl ester

[1596] The compound was prepared in a manner similar to Example 1 using2-pyridin-4-yl-thiazole-4-carbonyl azide and(6-amino-pyridin-2-ylmethyl)-isopropyl-carbamic acid tert-butyl ester toafford a white solid. MS m/z: 469.2 (M+H). Calc'd for C₂₃H₂₈N₆O₃S:468.19.

EXAMPLE 277

[1597]

[1598]1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1599] The compound was prepared in a manner similar to Example 2 togive a white solid. EI-MS m/z: 368.2 (M+H). Calc'd for C₁₈H₂₀N₆OS:368.14.

EXAMPLE 278

[1600]

[1601]Isopropyl-{6-[3-(2-phenyl-thiazol-4-yl)-ureido]-pyridin-2ylmethyl}-carbamicacid tert-butyl ester

[1602] The compound was prepared in a manner similar to Example 1 using2-phenyl-thiazole-4-carbonyl azide to afford a white solid. MS m/z:468.4 (M+H). Calc'd for C₂₄H₂₉N₅O₃S: 467.20.

EXAMPLE 279

[1603]

[1604]1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea

[1605] The compound was prepared in a manner similar to Example 2 togive a white solid. EI-MS m/z: 368.2 (M+H). Calc'd for C₁₉H₂₁N₅OS:367.15.

EXAMPLE 280

[1606]

[1607]{6-[3-(2-Chloro-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-isopropyl-carbamicacid t rt-butyl ester

[1608] The compound was prepared in a manner similar to Example 1 using2-chloro-thiazole-4-carbonyl azide to afford a white solid. MS m/z:426.3 (M+H). Calc'd for C₁₈H₂₄ClN₅O₃S: 425.13.

EXAMPLE 281

[1609]

[1610]1-(2-Chloro-thiazol-4-yl)-3-[6-(isopropylamino-methyl)-pyridin-2-yl]-urea

[1611] The compound was prepared in a manner similar to Example 2 togive a white solid. EI-MS m/z: 326.1 (M+H). Calc'd for C₁₃H₁₆ClN₅OS:325.08.

EXAMPLE 282

[1612]

[1613]{6-[3-(2-Bromo-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl}-isopropyl-carbamicacid tert-butyl ester

[1614] The compound was prepared in a manner similar to Example 1 togive a white solid. EI-MS m/z: 470.0 (M+H). Calc'd for C₁₈H₂₄BrN₅O₃S:469.08.

EXAMPLE 283

[1615]

[1616]1-(2-Bromo-thiazol-4-yl)-3-[6-(isopropylamino-methyl)-pyridin-2-yl]-urea

[1617] The compound was prepared in a manner similar to Example 2 togive a white solid. EI-MS m/z: 370.2 (M+H). Calc'd for C₁₃H₁₆BrN₅OS:369.03.

EXAMPLE 284

[1618]

[1619]1-(2-Bromo-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea

[1620] A stirred solution of 2-bromo-thiazole-4-carbonyl azide (0.10 g,0.43 mmol) in dry toluene (15 mL) was heated at 85° C. for 20 minfollowed by the addition of6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-ylamine (0.09 g, 0.43mmol). The resulting mixture was heated at 90° C. for 15 h. The mixturewas cooled to RT and concentrated. The residue obtained was washed withMeOH at RT. The impurities were dissolved in MeOH yielding a whiteprecipitate as the desired product. MS m/z: 412.2 (M+H). Calc'd forC₁₅H₁₈BrN₅O₂S: 411.04.

EXAMPLE 285

[1621]

[1622]1-(2-Chloro-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea

[1623] The compound was prepared in a manner similar to Example 15 using2-chloro-thiazole-4-carbonyl azide to afford a white solid. EI-MS m/z:368.2 (M+H). Calc'd for C₁₅H₁₈ClN₅O₂S: 367.09.

EXAMPLE 286

[1624]

[1625](6-{3-[2-(5-tert-Butyl-oxazol-2-yl)-thiazol-4-yl]-ureido}-pyridin-2-ylmethyl)-isopropyl-carbamicacid tert-butyl ester

[1626] A stirred solution of2-(5-tert-butyl-oxazol-2-yl)-thiazole-4-carbonyl azide (0.22 g, 0.79mmol) was heated at 85° C. for 25 min followed by the addition of(6-amino-pyridin-2-ylmethyl)-isopropyl-carbamic acid tert-butyl ester.The resulting solution was heated at 90° C. for 15 h. The mixture wasbrought to RT, concentrated and purified by chromatography on silica gelusing 2:1 Hexanes/EtOAc as eluent to afford a yellow solid as thedesired product. MS m/z: 515.4 (M+H). Calc'd for C₂₅H₃₄N₆O₄S: 514.24.

EXAMPLE 287

[1627]

[1628]1-[2-(5-tert-Butyl-oxazol-2-yl)-thiazol-4-yl]-3-[6-(isopropylamino-methyl)-pyridin-2-yl]-urea

[1629] The compound was prepared in a manner similar to Example 2 togive a white solid. EI-MS m/z: 415.30 (M+H). Calc'd for C₂₀H₂₆N₆O₂S:414.18.

EXAMPLE 288

[1630]

[1631]1-(2-phenylthiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea

[1632] 2-Phenyl-4-thiazolcarbonylazide (200 mg, 0.87 mmol) in drytoluene (5 mL) was heated to 105° C. under N₂ and maintained at for 5min. 2-Amino-6-(4-pyrrolidin-1-ylmethylphenoxy)pyridine was added andthe resulting mixture was heated at 105° C. for 4 h. After cooling toRT, the solid was filtered and rinsed with Et₂O. The product waspurified by chromatography on silica gel eluting with MeOH/CH₂Cl₂ (5%)to form a white solid. MS m/z: 472.3 (M+H). Calc'd for C₂₆H₂₅N₅O₂S:471.17.

EXAMPLE 289

[1633]

[1634]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-urea

[1635] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide and6-(Tetrahydro-furan-3-yloxy)-pyridin-2-ylamine were heated together intoluene to give1-(2-pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-ureaas a white solid. MS m/z: 384.3 (M+H). Calc'd for C₁₈H₁₇N₅O₃S 383.43.

EXAMPLE 290

[1636]

[1637]1-[2-(1H-Indazol-5-yl)-thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea

[1638] In manner similar to Example 234,2-(1-acetyl-1H-indazol-5-yl)thiazole-4-carbonyl azide and6-piperidin-1-ylmethyl-pyridin-2-ylamine were heated in toluene to give1-[2-(1-acetyl-1H-indazol-5-yl)-thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-ureaas a yellow solid (62 mg, 100%) which was next dissolved in EtOH (5 mL),treated with 1 N HCl (0.1 mL) and heated to 70° C. After 1 h, thereaction mixture was concentrated in vacuo and extracted with EtOAc,washed with saturated NaHCO₃ and brine, dried (MgSO₄) and concentratedin vacuo to give the desired compound as a tan solid. MS m/z: 434.3(M+H). Calc'd for C₂₂H₂₃N₇OS—433.53.

EXAMPLE 291

[1639]

[1640]1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1641] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide and1′-methyl-1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6yl amine were heatedtogether in toluene to give1-(1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-ureaas a tan solid. MS m/z: 393.0 (M+H). Calc'd. for C₂₀H₂₀N₆OS—392.48.

EXAMPLE 292

[1642]

[1643]1-(2-Bromo-thizol-4-yl)-3-(1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea

[1644] In a manner similar to Example 234, 2-bromo-thiazole-4-carbonylazide and 1′-methyl-1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6yl aminewere heated together in toluene to give1-(2-bromo-thizol-4-yl)-3-(1′-methyl-1′,2,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-ureaas a tan solid. MS m/z: 395.1 (M+H). Calc'd for C₁₅H₁₆BrN₅OS—394.29.

EXAMPLE 293

[1645]

[1646]1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-2[2,4]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea

[1647] In a manner similar to Example 234 2-phenyl-thiazole-4-carbonylazide and 1′-methyl-1′,2,3′,6′-tetrahdyro-[2,4′]bipyridinyl-6yl aminewere heated together in toluene to give1-(1′-methyl-1′,2′,3′,6′-tetrahydro-2[2,4]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-ureaas a tan solid. MS m/z: 392.3 (M+H). Calc'd for C₂₁H₂₁N₅OS 391.49.

EXAMPLE 294

[1648]

[1649]1-[6-(3-Hydroxy-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thizol-4-yl)-urea

[1650] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide andN-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diamine were heatedtogether in toluene to give1-[6-(3-hydroxy-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thizol-4-yl)-ureaas a yellow solid (65 mg, 16%) which was dissolved in MeOH (15 mL) andtreated with 10 mg of TsOH. The reaction was heated to reflux for 2 h,quenched with saturated NaHCO₃, extracted with EtOAc, washed with brinethen dried (MgSO₄)and concentrated in vacuo to give1-[6-(3-hydroxy-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thizol-4-yl)-ureaas a yellow solid. MS m/z: 371.2 (M+H). Calc'd for C₁₇H₁₈N₆O₂S—370.43.

EXAMPLE 295

[1651]

[1652]1-(2-Bromo-thiazol-4-yl)-3-[6(3-hydroxy-propylamino)-pyridin-2-yl]-urea

[1653] In a manner similar to example 299, 2-bromo-thiazole-4-carbonylazide and N-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyridine-2,6-diaminewere heated together in toluene to give1-(2-bromo-thiazol-4-yl)-3-{6-[3-(tetrahydro-pyran-22-yloxy)-propylamino]-pyridin-2-yl}-urea as a yellow solid (150 mg, 75%)which was then dissolved in MeOH (15 mL) and treated with 10 mg of TsOH.Heated to reflux for 2 h, quenched with saturated NaHCO₃, extracted withEtOAc and washed with brine then dried (MgSO₄)and concentrated in vacuoto give1-(2-bromo-thiazol-4-yl)-3-[6(3-hydroxy-propylamino)-pyridin-2-yl]-ureaas a white solid. MS m/z: 373.2 (M+H). Calc'd for C₁₂H₁₄BrN₅O₂S—372.24.

EXAMPLE 296

[1654]

[1655]1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipydrinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1656] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide and1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-ylamine wereheated together in toluene to give1-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipydrinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-ureaas a yellow solid. MS m/z: 395.0 (M+H). Calc'd. for C₂₀H₂₂N₆OS—394.49.

EXAMPLE 297

[1657]

[1658]1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea

[1659] In a manner similar to Example 234 2-phenyl-thiazole-4-carbonylazide and1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-ylamine wereheated together in toluene to give1-(1′-methyl-1′,2′,3′,4′,5′,6′-hexahydro[2,4′]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-ureaas a white solid. MS m/z: 394.3 (M+H). Calc'd for C₂₁H₂₃N₅OS—393.51.

EXAMPLE 298

[1660]

[1661]6-[3-(2-Pyridin-4-yl-thizol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylicacid tert-butylester

[1662] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide and6-amino-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester were heated together in toluene to give6-[3-(2-pyridin-4-ylthizol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylicacid tert-butyl ester as a yellow solid. MS m/z: 479.1 (M+H). Calc'd forC₂₄H₂₆N₆O₃S 478.57.

EXAMPLE 299

[1663]

[1664]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea

[1665]6-[3-(2-Pyridin-4-yl-thizol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylicacid tert-butyl ester was suspended in CH₂Cl₂ (10 mL) and treated withTFA (5 mL). Stirred at RT for 30 min. Quenched with saturated NaHCO₃ andfiltered yellow solid. Washed solid with H₂O and MeOH to give1-(2-pyridin-4-yl-thiazol-4-yl)-3-(1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-ureaas a yellow solid. MS m/z: 379.1 (M+H). Calc'd for C₁₉H₁₈N₆OS—378.45.

EXAMPLE 300

[1666]

[1667]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-2-ylmethoxy)-pyridin-2-yl]-urea

[1668] In a manner similar to Example 2342-(4-pyridinyl)-4-thiazolcarbonylazide and6-(tetrahydro-furan-2ylmethoxy)-pyridin-2ylamine were heated together intoluene to give1(2-pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-2-ylmethoxy)-pyridin-2-yl]-ureaas a yellow solid. MS m/z: 398.4 (M+H). Calc'd for C₁₉H₁₉N₅O₃S—397.45.

EXAMPLE 301

[1669]

[1670]1-(2-Pyridin-4-yl-thizol-4-yl)-3-[6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-yl]-urea

[1671] In a manner similar to Example 234,2-(4-pyridinyl)-4thiazolcarbonylazide and6-(tetrahydro-furan-3ylmethoxy)-pyridin-2ylamine were heated together intoluene to give1-(2-pyridin-4-yl-thizol-4-yl)-3-[6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-yl]-ureaas a yellow solid. MS m/z: 398.3 (M+H). Calc'd. for C₁₉H₁₉N₅O₃S—397.45.

EXAMPLE 302

[1672]

[1673] 1-(2-Pyridin-4-yl-thiazol-4-yl)-3-pyrimidin-2-yl-urea

[1674] In a manner similar to Example 2342-(4-pyridinyl)-4-thiazolcarbonylazide and 2-aminopyrimidine were heatedtogether in toluene to give1-(2-pyridin-4-yl-thiazol-4-yl)-3-pyrimidin-2-yl-urea as a yellow solid.MS m/z: 299.1 (M+H). Calc'd for C₁₃H₁₀N₆OS—298.32.

EXAMPLE 303

[1675]

[1676] 1-(4-Methyl-pyrimidin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1677] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide and 2-amino-4-methyl-pyrimidinewere heated together in toluene to give1-(4-methyl-pyrimidin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea as ayellow solid. MS m/z: 313.1 (M+H). Calc'd for C₁₄H₁₂N₆OS 312.35.

EXAMPLE 304

[1678]

[1679]2-[6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

[1680] In a manner similar to Example 234,2-(4-pyridinyl)-4-thiazolcarbonylazide and2-(6-amino-pyridin-2yloxymethyl)-pyrrolidine-1-carboxylic acidtert-butyl ester were heated together in toluene to give1-(2-pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-ureaas a yellow solid. MS m/z: 497.4 (M+H). Calc'd for C₂₄H₂₈N₆O₄S—496.58.

EXAMPLE 305

[1681]

[1682]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-ureaTo a solution of1-(2-pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-ureaand 150 ml of CH₂Cl₂ was added 50 mL of TFA. Stirred at RT for 30 min,then concentrated in vacuo. Neutralized with saturated NaHCO₃ andbasified to pH 9. Filtered white precipitate and washed with H₂O andEt₂O. Dried on high-vacuum to give1-(2-pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-ureaas an off-white solid. MS m/z: 497.4 (M+H). Calc'd forC₁₉H₂₀N₆O₂S—396.47.

EXAMPLE 306

[1683]

[1684] 6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridine-2-carbothioicacid diethylamide

[1685] MS m/z: 413.0 (M+H). Calc'd. for C₁₉H₂₀N₆OS₂—412.11.

EXAMPLE 307

[1686]

[1687]1-(2-Bromo-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea

[1688] MS m/z: 410.3 (M+H). Calc'd. for C₁₆H₂₀BrN₅OS—409.06.

EXAMPLE 308

[1689]

[1690]1-(2-Chloro-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea

[1691] MS m/z: 366.2 (M+H). Calc'd. for C₁₆H₂₀ClN₅OS—365.1.

EXAMPLE 309

[1692]

[1693]1-(2-Phenyl-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea

[1694] MS m/z: 408.3 (M+H). Calc'd for C₂₁H₂₁N₅O₂S—407.49.

EXAMPLE 310

[1695]

[1696]1-(2-Bromo-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea

[1697] MS m/z: 412.0 (M+2H). Calc'd for C₁₅H₁₆BrN₅O₂S—410.29.

EXAMPLE 311

[1698]

[1699]1-(2-Phenyl-thiazol-4-yl)-3-(4-piperidin-1-ylmethyl-pyridin-2-yl)-urea

[1700] MS m/z: 394.3 (M+H). Calc'd for C₂₁H₂₃N₅OS—393.51.

EXAMPLE 312

[1701]

[1702]1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-phenoxy-pyridin-2-yl)-urea

[1703] MS m/z: 420.1 (M+H). Calc'd for C₂₁H₁₇N₅O₃S—419.46.

EXAMPLE 313

[1704]

[1705]1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea

[1706] MS m/z: 441.0 (M+H). Calc'd for C₂₁H₂₄N₆O₃S—440.52.

EXAMPLE 314

[1707]

[1708]1-[6-(2-Dimethylamino-ethoxy)-pyridin-2-yl]-3-[2-(2-methoxy-pyridin-4-yl)-thiazol-4-yl]-urea

[1709] MS m/z: 415.0 (M+H). Calc'd for C₁₉H₂₂N₆O₃S—414.48.

EXAMPLE 318

[1710]

[1711]1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-(2-methyl-thiazol-4-yl)-urea

[1712] MS m/z: 348.1 (M+H). Calc'd for C₁₆H₂₁N₅O₂S—347.44.

EXAMPLE 316

[1713]

[1714]1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1715] MS m/z: 411.1 (M+H). Calc'd for C₂₀H₂₂N₆O₂S—410.49.

EXAMPLE 317

[1716]

[1717]1-(2-phenylthiazol-4-yl)-3-(6-pyrrolidin-1-ylmethyl-pyridin-2-yl)urea

[1718] EI-MS m/z 380.4 (M+H). Calc'd for C₂₀H₂₁N₅OS: 379.15.

EXAMPLE 318

[1719]

[1720] 1-(6-Diethylaminomethylpyridin-2-yl)-3-(2-phenylthiazol-4-yl)urea

[1721] EI-MS m/z 382.2(M+H). Calc'd for C₂₀H₂₃N₅OS: 381.16.

EXAMPLE 319

[1722]

[1723](S)-1-[6-(1-Methylpyrrolidin-2-ylmethoxy)pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea

[1724] EI-MS m/z 410.0 (M+H). Calc'd for C₂₁H₂₃N₅O₂S: 409.16.

EXAMPLE 320

[1725]

[1726] tert-Butyl4-(2-{6-[3-(2-phenylthiazol-4-yl)-ureido]pyridin-2-yloxy}ethyl)piperidine-1-carboxylate

[1727] MS m/z: 524.3 (M+H). Calc'd for C₂₇H₃₃N₅O₄S: 523.23

EXAMPLE 321

[1728]

[1729]1-[6-(2-Piperidin-4-yl-ethoxy)pyridin-2-yl]-3-[2-phenylthiazol-4-yl]urea

[1730] MS m/z: 424.1 (M+1). Calc'd for C₂₂H₂₅N₅O₂S: 423.17.

EXAMPLE 322

[1731]

[1732]1-[6-(4-Ethylpiperazin-1-yl)-pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea

[1733] EI-MS m/z 419.3 (M+H). Calc'd for C₂₁H₂₄N₆OS: 408.17.

EXAMPLE 323

[1734]

[1735]1-[6-(4-Pyridin-2-yl-piperazin-1-yl)pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea

[1736] EI-MS m/z 458.2 (M+H). Calc'd for C₂₄H₂₃N₇OS: 457.17.

EXAMPLE 324

[1737]

[1738]1-(2-phenylthiazol-4-yl)-3-[6-(4-pyrimidin-2-yl-piperazin-1-yl)pyridin-2-yl]urea

[1739] EI-MS m/z 459.4 (M+H). Calc'd for C₂₃H₂₂N₈OS: 458.16.

EXAMPLE 325

[1740]

[1741] Diethyl 6-[3-(2-phenylthiazol-4-yl)ureido]-pyridine-2-carboxamide

[1742] EI-MS m/z 396.3 (M+H). Calc'd for C₂₀H₂₁N₅O₂S: 395.14.

EXAMPLE 326

[1743]

[1744]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea

[1745] EI-MS m/z 473.3(M+H). Calc'd for C₂₅H₂₄N₆O₂S: 472.17.

EXAMPLE 327

[1746]

[1747]1-(2-Bromothiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea

[1748] MS m/z: 473.9 (M+H). Calc'd for C₂₀H₂₀BrN₅O₂S: 473.05.

EXAMPLE 328

[1749]

[1750]4-{6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-piperidine-1-carboxylicacid tert-butyl ester

[1751] MS m/z: 511.2 (M+H). Calc'd for C₂₅H₃₀N₆O₄S—510.61.

EXAMPLE 329

[1752]

[1753]1-[6-(Piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1754] MS m/z: 411.0 (M+H). Calc'd for C₂₀H₂₂N₆O₂S—410.49.

EXAMPLE 330

[1755]

[1756]1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1757] MS m/z: 425.2 (M+H). Calc'd for C₂₁H₂₄N₆O₂S—424.52.

EXAMPLE 331

[1758]

[1759]1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1760] MS m/z: 411.0 (M+H). Calc'd for C₂₀H₂₂N₆O₂S—410.49.

EXAMPLE 332

[1761]

[1762]1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1763] MS m/z: 397.3 (M+H). Calc'd for C₁₉H₂₀N₆O₂S—396.47.

EXAMPLE 333

[1764]

[1765]3-(6-[3-(2-Phenyl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-azetidine-1-carboxylicacid tert-butyl ester

[1766] MS m/z: 482.4 (M+H). Calc'd for C₂₄H₂₇N₅O₄S—481.57.

EXAMPLE 334

[1767]

[1768]1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea

[1769] MS m/z: 382.3 (M+H). Calc'd for C₁₉H₁₉N₅O₂S—381.45.

EXAMPLE 335

[1770]

[1771]1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea

[1772] MS m/z: 396.3 (M+H). Calc'd for C₂₀H₂₁N₅O₂S—395.48.

EXAMPLE 336

[1773]

[1774]4-{6-[3-(2-Phenyl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-piperidine-1-carboxylicacid tert-butyl ester

[1775] MS m/z: 510.3 (M+H). Calc'd for C₂₆H₃₁N₅O₄S—509.62.

EXAMPLE 337

[1776]

[1777]1-(2-Phenyl-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea

[1778] MS m/z: 410.3 (M+H). Calc'd for C₂₁H₂₃N₅O₄S—409.51.

EXAMPLE 338

[1779]

[1780]1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea

[1781] MS m/z: 424.2 (M+H). Calc'd for C₂₂H₂₅N₅O₂S—423.53.

EXAMPLE 339

[1782]

[1783]1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea

[1784] MS m/z: 410.4 (M+H). Calc'd for C₂₁H₂₃N₅O₂S—409.51.

EXAMPLE 340

[1785]

[1786]1-[6-(2-Piperidin-4-yl-ethoxy)-pyridin-2-yl]-3-(2-thiophen-2-yl-thiazol-4-yl)-urea

[1787] MS m/z: 430.1 (M+H). Calc'd for C₂₀H₂₃N₅O₂S₂—429.56.

EXAMPLE 341

[1788]

[1789]1-[2-(5-tert-Butyl-oxazol-2-yl)-thiazol-4-yl]-3-[6-(2piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea

[1790] MS m/z: 471.1 (M+H). Calc'd for C₂₃H₃₀N₆O₃S—470.59.

EXAMPLE 342

[1791]

[1792]1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-[2-(thiophene-2-sulfonylmethyl)-thiazol-4-yl]-urea

[1793] MS m/z: 494.0 (M+H). Calc'd for C₂₀H₂₃N₅O₄S₃—493.63.

EXAMPLE 343

[1794]

[1795]1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea

[1796] MS m/z: 425.1 (M+H). Calc'd for C₂₁H₂₄N₆O₂S—424.52.

EXAMPLE 344

[1797]

[1798][2-(2-Chloropyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea

[1799] MS m/z: 429.1 (M+H). Calc'd for C₂₀H₂₁ClN₆OS—428.9.

[1800] The following compounds can be made by procedures similar tothose previously described:

[1801] tert-Butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-pyrrolidine-1-carboxylate

[1802]1-{6-[1-(1-Methyl-1H-pyrrole-2-carbonyl)-pyrrolidin-3-ylmethoxyl]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1803]1-{6-[1-(2-tert-Butyl-5-methyl-2H-pyrazole-3-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1804]1-{6-[1-(1H-Indole-2-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1805]1-{6-[1-(1H-Indole-3-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4yl)-urea

[1806]1-{6-[1-(2-1H-Indol-3-yl-acetyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1807]1-{6-[1-(1H-Indole-5-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1808]1-{6-[1-(1-Methyl-1H-indole-2-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4yl-thiazol-4-yl)-urea

[1809]1-(6-{1-[2-(2-Methyl-1H-indol-3-yl)-acetyl]-pyrrolidin-3-ylmethoxy}-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1810]1-{6-[1-(3-Methyl-3H-imidazole-4-sulfonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1811]1-{6-[1-(Pyridine-3-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1812]1-{6-[1-(3,5-Dimethyl-isoxazole-4-sulfonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1813]1-{6-[1-(1-Methyl-piperidine-3-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4yl)-urea

[1814] 1-[6-(1-M thanesulfonyl-pyrrolidin-3-ylmthoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1815]4-(3-{6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-pyrrolidine-1-carbonyl)-benzenesulfonamide

[1816]1-{6-[1-(1-Methyl-piperidine-4-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1817] tert-Butyl3-(3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]pyridin-2-yloxymethyl}-pyrrolidine-1-carbonyl)-piperidine-1-carboxylate

[1818]1-{6-[1-(1-Methyl-1H-indole-2-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4yl)-urea

[1819]1-{6-[1-(2-Ethyl-5-methyl-2H-pyrazole-3-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1820]1-{6-[1-(1H-Benzoimidazole-5-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4yl-thiazol-4yl)-urea

[1821]1-(6-{1-[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4carbonyl]-pyrrolidin-4-carbonyl]-pyrrolidin-3-ylmethoxy}-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1822]1-{6-[1-(1-Acetyl-piperidine-4-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)urea

[1823]1-{6-[1-(Pyridine-2-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4yl)-urea

[1824]1-{6-[1-(2-Methoxy-pyridine-3-carbonyl)-pyrrolidin-3ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1825]1-{6-[1-(6-Oxo-1,4,5,6-tetrahydro-pyridazine-3-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1826]1-{6-[1-(1-Acetyl-pyrrolidine-2-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl]-urea

[1827]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-{6-[1-(tetrahydro-furan-3-carbonyl)-pyrrolidin-3-ylmethoxy]-pyridin-2-yl}-urea

[1828]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-3-yloxy)-pyridin-2-yl]-urea

[1829]1-[6-(1-Methyl-pyrrolidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1830]1-[6-(Piperidin-2-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4yl-thiazol-4-yl)-urea

[1831]1-[6-(1-Methyl-piperidin-2-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1832]1-{6-[1-(4-Methoxy-benzyl)-piperidin-2-ylmethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1833]1-[6-(Piperazin-2-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1834]1-[6-(Morpholin-3-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1835]1-{6-[(Morpholin-3-ylmethyl)-amino]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1836]1-{6-[(Piperazin-2-ylmethyl)-amino]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1837]1-[2-(6-Amino-pyridin-3-yl)-thiazol-4-yl]-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea

[1838]1-[6-(Methyl-morpholin-3-ylmethyl-amino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1839]1-[6-(Methyl-piperazin-2-ylmethyl-amino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1840]1-[6-(2-Piperidin-1-yl-ethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1841]1-[6-(2-Dimethylamino-1-methyl-ethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1842]1-[6-(2-Diisopropylamino-ethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1843]1-{6-[2-(2-Oxo-pyrrolidin-1-yl)-ethoxy]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1844]1-[6-(1-Benzyl-pyrrolidin-3-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1845]1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-3-yloxy)-pyridin-2-yl]-urea

[1846]1-[6-(1-Benzyl-piperidin-3-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1847]1-[6-(Piperidin-3-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea

[1848]1-[2-(2-Amino-pyridin-4-yl)-thiazol-4-yl]-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea

[1849]1-[2-(2-Amino-pyrimidin-5-yl)-thiazol-4-yl]-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea.

[1850] The pharmacological properties of the compounds of this inventionmay be confirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which follow have been carried out with thecompounds according to the invention and their salts. The compounds ofinvention exhibited more than 10% cdk5/p25 or cdk2/cyclin inhibition at10 μM.

[1851] Biological Evaluation

[1852] Protocals for Cyclin E2/CDK2

[1853] Cloning of Cdk2 and cyclin 2/Generation of Cdk2 and cyclin 2Recombinant Baculovirus

[1854] The following oligonucleotide primers flanking the codingsequence of the human Cdk2 cDNA clone were used to amplify the gene andplace EcoRI and HindIII restriction sites at the 5′ and 3′ ends of thegene respectively. [5′oligo-5′-AAGCGCGCGGAATTCATAAATATGGAGAACTTCCAAAAGGTGGAA-3′; 3′oligo-5′-CTCGACAAGCTTATTAGAGTCGAAGATGGGGTAC-3′]

[1855] The following oligonucleotide primers flanking the codingsequence of the human CycE2 cDNA clone were used to amplify the gene andplace XhoI and SphI restriction sites at the 5′ and 3′ ends of the generespectively. A His tag was also placed at the N-terminus of the CycE2protein. [5′oligo-5′-CCCGGGATCTCGAGATAAATATGCATCATCATCATCATTCAAGACGAAGTAGCCGTTTACAA-3′; 3′ oligo-5′-CCCGGTACCGCATGCTTAGTGTTTTCCTGGTGGTTTTTC-3′]

[1856] CycE-2 and Cdk2 PCR fragments were subcloned into the vectorpFastBacDual (Gibco/LifeTechnologies) using the restriction sitesindicated above. Recombinant virus was made following protocols suppliedby the manufacturer.

[1857] Expression of Cyclin 2/CDK2 in Insect Cells

[1858] Hi5 cells were grown to a cell density of 1×10⁶ cells per ml in800 ml of Excell 405 media (JRH). Cells were infected with virus at amultiplicity of 1. Infected cultures were incubated with shaking at 28°C. Cells were harvested by centrifugation.

[1859] Cloning of Cdk5 and p25/Generation of CDK5 and p25 RecombinantBaculovirus

[1860] Based on the reported sequences of human CDK5 and p35, GenBankaccession numbers X66364 and X80343 respectively, oligonucleotideprimers flanking the coding sequence of each gene were used to amplifyCDK5 (5′-GCGATGCAGAAATACGAGAAACT-3′; 5′-CCCCACTGTCTCACCCTCTCAA-3′) andp35 (5′-CGGTGAGCGGTTTTATCCC-TCC-3′; 5′-GCATTGAATCCTTGAGCCATGACG-3′) froma human fetal brain cDNA library (Clontech). p25, a C-terminalproteolytic fragment corresponding to amino acids 99-307 of full-lengthp35 (Lew, et. al), was PCR subcloned from the p35 sequence usingoligonucleotide primers (5′-CGGGATCCATGGCCCAGCCCCCACCGGCCCA-3′;5′-CCAAGCTTTCACCGATCCAGGCCTAG-3′). The p25 PCR product (629 bp) wascloned into the pFastBacHTb baculovirus expression vector (Gibco BRL)using BamHI and HindIII. CDK5 was PCR subcloned using oligonucleotideprimers (5′-CGGGATCC-GCCACCATGCAGAAATACGAGAAACTGG-3′;5′-GGACTAGTCTAGGGCGGAC-AGAAGTCG-3′). The CDK5 PCR product (879 bp) wascloned into the pFastBac1 baculovirus expression vector (Gibco BRL)using BamHI and SpeI. Recombinant baculovirus expressing human Cdk5 andN-terminally six histidine tagged p25 were generated using theBac-to-Bac system (Gibco BRL).

[1861] Expression of P25/CDK5 in Insect Cells

[1862] Coinfections of Hi5 cells by recombinant baculovirus containingthe P25 gene and another containing the CDK5 gene were done at amultiplicity of infection of 5 (each virus). The Hi5 cultures were setto a cell concentration of 1×10⁶ cells per ml in 800 ml of Excell mediaby JRH. The cultures were grown in 2.6L fernbach flasks with shaking(110 rpm) at 27° C. for 60 h. The cells were harvested bycentrifugation.

[1863] Purification of Complexes

[1864] All steps were performed at 4° C. Insect cells expressing eithercyclin E2/CDK2 or p25/CDK5 were lysed using a microfluidizer(Microfluidics Corporation.) The lysis buffer contained 10 mM Hepes, 150mM NaCl, 20 mM MgCl₂, 20 mm imidazole, 0.5 mM EDTA, 10% glycerol, 25μg/ml Aprotinin, 25 μg/ml Leupeptin, 1 mM Pefabloc, pH 7.5). Totalprotein was determined on the resulting lysate using the Bradford methodwith a BSA standard curve. Protamine sulfate was added to the lysate togive a final 30:1 protein:protamine sulfate, incubated for 15-20 min andcentrifuged at 14000×g for 30 min to remove insoluble material. Ni—NTAsuperflow resin (Qiagen Inc) was equilibrated in lysis buffer andincubated with the centrifugation supernatant for 1 h while rotating.The slurry was packed in a glass column and washed until a stable UVbaseline was reached. Proteins were eluted with a linear gradient of20-300 mM imidazole over 15 column volumes. Fractions were analyzed bySDS-PAGE and Western blot. Appropriate fractions were pooled, totalprotein determined, and submitted for kinase assay.

[1865] CDK2 Kinase Assay

[1866] CDK2 kinase assays were carried out with inhibitor (dissolved inDMSO) in a total volume of 50 μl with 1 nM enzyme (His-tagged cyclin2/CDK2), 1 μM Histone-H1 (Gibco), 25 μM ATP, 20 μCi/ml ³³P-ATP(Amersham; 2500 Ci/mmole) in kinase buffer (50 mM Tris-HCl, pH 7.5, 5 mMMgCl₂, 1 mM EGTA, 5 mM DTT, 200 μg/ml BSA and 20 mM β-glycerophosphatefor 60 min at 25° C. Reactions were stopped by the addition of an equalvolume of 30% trichloroacetic acid (Sigma). Precipitates were formed byincubation at 4° C. for 60 min then collected by filtration onMillipore® filter plates (MAFC NOB10). MicroScint-20 (40 μL, Packard)was added, and counted on a Packard TopCount®. Raw cpms were analyzedwith a four-parameter logistic fit using the Levenburg Marquardtalgorithm (X1fit software IDBS LTD). Kinetic parameters were calculatedby non-linear regression analysis using Grafit (Erithacus Software LTD).Riscovitine (BIOMOL Research Labs Inc., Plymouth Meeting, Pa.) andstaurosporin (Sigma, St. Louis Mo.) were used as standards.

[1867] CDK5 Kinase Assay

[1868] CDK5 kinase assays were carried out with inhibitor (dissolved inDMSO) in a total volume of 50 μl with 1 nM enzyme (His-tagged p25/CDK5),1 μM Histone-H1 (Gibco), 25 μM ATP, 20 μCi/ml ³³P-ATP (Amersham; 2500Ci/mmole) in kinase buffer (50 mM Tris-HCl, pH 7.5, 5 mM MgCl2, 1 mMEGTA, 5 mM DTT, 200 μg/ml BSA and 20 mM β-glycerophosphate) for 60 minat 25° C. Reactions were stopped by the addition of an equal volume of30% trichloroacetic acid (Sigma). Precipitates were formed by incubationat 4° C. for 60 min then collected by filtration on Millipore® filterplates (MAFC NOB10). MicroScint-20 (40 μL, Packard) was added, andcounted on a Packard TopCount®. Raw cpms were analyzed with afour-parameter logistic fit using the Levenburg Marquardt algorithm(X1fit software IDBS LTD). Kinetic parameters were calculated bynon-linear regression analysis using Grafit (Erithacus Software LTD).Riscovitine (BIOMOL Research Labs Inc., Plymouth Meeting, Pa.) andstaurosporin (Sigma) were used as standards.

[1869] Examples 235-236, 238, 242, 245, 247-251, 258, 263-268, 270,273-275, 279, 280-282, 287-288, 291-302, 304, 307-311, 316-317, 319-322,324-325, 327-330, 332-335, 337-338, 340-343, and 346-347 exhibitedcdk2/cyclin kinase activity with IC₅₀ values less than 0.5 μM. Thecompounds of examples 235-240, 242, 245, 247-251, 258, 263-268, 273-275,280, 282, 286-288, 291-302, 304, 307-313, 315-317, 319-322, 324-325,328-330, 332-335, 337-338, 340-343, and 345-347 exhibited cdk5/p25kinase activity with IC₅₀ values less than 0.5 μM.

[1870] Cell Proliferation Assay

[1871] Cell proliferation was measured using a calorimetric immunoassay(B/M Roche #164 7229), based on the measurement of pyrimidine analogBrdU incorporation during DNA synthesis in proliferating cells. Cells,e.g., human PC-3 prostate carconima cells, huFSF normal human foreskinfibroblast cells, HCT 116 human colon carcinoma cells or HT 29 humancolon carcinoma cells, were cultured in a 96-well plate for 24 h, untila cell count of 3×10³ to 6×10³ cells per well in duplicate wells wereachieved, in a well volume of 200 μl. The media was changed and 1 μl of200× control inhibitors or compounds was added to each well. Cells areincubated for 48 h at 37° C. The cells were labeled with BrdU for 4 h at37° C. The labeling medium was removed and in one step, the cells werefixed and the DNA was denatured (30 min at RT). Anti-BrdU-POD antibodywas added to bind to the BrdU incorporated in newly synthesized cellularDNA (60-90 min at RT). The cells were washed 3× with washing buffer,substrate (100 μl) was added and the cells were incubated for 10 min atRT. The substrate reaction was stopped by adding 25 μl of 1M H₂SO₄. Theamount of BrdU incorporated was quantified by measuring the absorbanceat 450 nm using ELISA reader. IC₅₀'s were calculated using GraFit(Sigma).

[1872] Ischemic Stroke Model: Middle Cerebral Artery Occlusion (MCAO) invivo

[1873] The compounds' effect on treating stroke was measured in a MCAOrat model. (L. Belayev et al., Stroke, 27, 1616-23 (1996). MaleSprague-Dawley rats (300-330 g body weight) were anesthetized withhalothane and MCAo was induced by inserting a poly-L-lysine coatedmonofilament suture to the beginning of the middle cerebral artery(MCA). After various time points (60, 90 or 120 min), the intraluminalsuture was carefully removed to start reperfusion. Physiologicalconditions (blood O₂, CO₂, pH, glucose, blood pressure) were monitoredand kept stable during the surgery. The compound was dissolved in 20%Captisol in phosphate buffered saline and administered (orally, IV orIP) 90 min after ischemia onset, at the beginning of reperfusion.Further dosing occurred at 4-8 h and twice a day thereafter.

[1874] The use of behavioral tests was directly analogous to theclinical neurological examination for assessing ischemic deficits andrates of behavioral recovery. The battery consisted of four tests: (1)postural reflex test, (2) forelimb placing test (J B Bederson et al.,Stroke, 17:472-76 (1986) (L. Belayev et al., Stroke, 26:2313-20 (1995),(3) contralateral foot fault index (A. Tamura et al., J. Cereb BloodFlow Metab., 1:53-60 (1981) (D M Freeney, Science, 217:855-57 (1982),and (4) cylinder asymmetry (T A Jones and T. Schallert, J. Neurosci.,14:2140-52 (1994). Tests were performed once a day for three days andthen once a week for a period of 30 days. These tests are useful inassessing neurological deficits for short-term studies; the cylinderasymmetry test appeared to be the most useful for long term experiments.

[1875] At the end of the experiment, the infarct volume was measured (JB Bederson et al., Stroke, 17:1304-8 (1986) (K A Osborne et al, J.Neurol Neurosurg. Psychiatry, 50:402 (1987) (R A Swanson et al., J.Cereb. Blood Flow Metab., 10:290-3 (1990). The brains were removed andsliced coronally at 1 mm thickness. The brain slices were stained with2% (w/vol) 2,3,5-triphenyltetrazolium chloride (TTC) which stains theinfarcted areas of the brain in white and allows for the measurement ofinfarct volume by an image-analysis system. Edema volume thatcontributes to infarct volume was subtracted by comparison with thetotal volume of the contralateral hemisphere.

[1876] Formulations

[1877] Also embraced within this invention is a class of pharmaceuticalcompositions comprising the active compounds of Formula I-V inassociation with one or more non-toxic, pharmaceutically-acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as “carrier” materials) and, if desired, other activeingredients. The active compounds of the present invention may beadministered by any suitable route, preferably in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. The compounds and compositions ofthe present invention may, for example, be administered orally,mucosally, topically, rectally, pulmonarily such as by inhalation spray,or parentally including intravascularly, intravenously,intraperitoneally, subcutaneously, intramuscularly intrasternally andinfusion techniques, in dosage unit formulations containing conventionalpharmaceutically acceptable carriers, adjuvants, and vehicles.

[1878] The pharmaceutically active compounds of this invention can beprocessed in accordance with conventional methods of pharmacy to producemedicinal agents for administration to patients, including humans andother mammals.

[1879] For oral administration, the pharmaceutical composition may be inthe form of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,preferably from about 1 to 500 mg, more preferably from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods.

[1880] The amount of compounds which are administered and the dosageregimen for treating a disease condition with the compounds and/orcompositions of this invention depends on a variety of factors,including the age, weight, sex and medical condition of the subject, thetype of disease, the severity of the disease, the route and frequency ofadministration, and the particular compound employed. Thus, the dosageregimen may vary widely, but can be determined routinely using standardmethods. A daily dose of about 0.01 to 500 mg/kg body weight, preferablybetween about 0.5 and about 50 mg/kg body weight and most preferablybetween about 0.1 to 20 mg/kg body weight, may be appropriate. The dailydose can be administered in one to four doses per day.

[1881] For therapeutic purposes, the active compounds of this inventionare ordinarily combined with one or more adjuvants appropriate to theindicated route of administration. If administered per os, the compoundsmay be admixed with lactose, sucrose, starch powder, cellulose esters ofalkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesiumstearate, magnesium oxide, sodium and calcium salts of phosphoric andsulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropylmethyl cellulose.

[1882] In the case of psoriasis and other skin conditions, it may bepreferable to apply a topical preparation of compounds of this inventionto the affected area two to four times a day.

[1883] Formulations suitable for topical administration include liquidor semi-liquid preparations suitable for penetration through the skin(e.g., liniments, lotions, ointments, creams, or pastes) and dropssuitable for administration to the eye, ear, or nose. A suitable topicaldose of active ingredient of a compound of the invention is 0.1 mg to150 mg administered one to four, preferably one or two times daily. Fortopical administration, the active ingredient may comprise from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of the formulation, althoughit may comprise as much as 10% w/w, but preferably not more than 5% w/w,and more preferably from 0.1% to 1% of the formulation.

[1884] When formulated in an ointment, the active ingredients may beemployed with either paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example at least 30% w/w of a polyhydric alcoholsuch as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,polyethylene glycol and mixtures thereof. The topical formulation maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs.

[1885] The compounds of this invention can also be administered by atransdermal device. Preferably transdermal administration will beaccomplished using a patch either of the reservoir and porous membranetype or of a solid matrix variety. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

[1886] The oily phase of the emulsions of this invention may beconstituted from known ingredients in a known manner. While the phasemay comprise merely an emulsifier, it may comprise a mixture of at leastone emulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include Tween 60, Span 80, cetostearyl alcohol,myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryldistearate alone or with a wax, or other materials well known in theart.

[1887] The choice of suitable oils or fats for the formulation is basedon achieving the desired cosmetic properties, since the solubility ofthe active compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

[1888] Formulations suitable for topical administration to the eye alsoinclude eye drops wherein the active ingredients are dissolved orsuspended in suitable carrier, especially an aqueous solvent for theactive ingredients. The active ingredients are preferably present insuch formulations in a concentration of 0.5 to 20%, advantageously 0.5to 10% and particularly about 1.5% w/w.

[1889] Formulations for parenteral administration may be in the form ofaqueous or non-aqueous isotonic sterile injection solutions orsuspensions. These solutions and suspensions may be prepared fromsterile powders or granules using one or more of the carriers ordiluents mentioned for use in the formulations for oral administrationor by using other suitable dispersing or wetting agents and suspendingagents. The compounds may be dissolved in water, polyethylene glycol,propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesameoil, benzyl alcohol, sodium chloride, tragacanth gum, and/or variousbuffers. Other adjuvants and modes of administration are well and widelyknown in the pharmaceutical art. The active ingredient may also beadministered by injection as a composition with suitable carriersincluding saline, dextrose, or water, or with cyclodextrin (ie.Captisol), cosolvent solubilization (ie. propylene glycol) or micellarsolubilization (ie. tween 80).

[1890] The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally acceptablediluent or solvent, for example as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

[1891] For pulmonary administration, the pharmaceutical composition maybe administered in the form of an aerosol or with an inhaler includingdry powder aerosol.

[1892] Suppositories for rectal administration of the drug can beprepared by mixing the drug with a suitable nonirritating excipient suchas cocoa butter and polyethylene glycols that are solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum and release the drug.

[1893] The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[1894] The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

[1895] From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

[1896] All mentioned references, patents, applications and publications,are hereby incorporated by reference in their entirety, as if herewritten.

What is claimed is:
 1. A compound of formula VI

wherein R¹⁵ is one or more substituents selected from H, optionallysubstituted heterocyclyl, phenyl, C₁-C₃-alkyl, C₁-C₂-haloalkyl,C₁-C₄-hydroxyalkyl, amino, C₁-C₄azidoalkyl, C₁-C₄-cyanoalkyl,C₁-C₄-aminoalkyl, halo, hydroxy, (optionally substitutedheterocyclyl)-C₁-C₄alkyl, optionally substituted phenoxy-C₁-C₂-alkyl,C₁-C₄alkoxy-C₁-C₄-alkyl, C₁-C₄-alkylamino-C₁-C₄-alkyl,C₁-C₄hydroxyalkylamino, amino-C₁-C₄-alkoxy-C₁-C₄-alkyl, optionallysubstituted heterocyclyloxy, optionally substitutedheterocyclyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy, optionallysubstituted phenoxy, C₁-C₄-alkoxycarbonyl, 5-6-memberedheterocyclyl-C₁-C₄-alkylaminocarbonyl, 5-6-membered N-containingheterocyclylcarbonyl, C₁-C₄-alkylaminocarbonyl,C₁-C₄-alkylaminothiocarbonyl, C₁-C₄-alkylamino-C₁-C₄-alkylaminocarbonyl,aminocarbonyl, 5-6-membered N-containingheterocyclyl-sulfonyl-C₁-C₄-alkyl, 5-6-membered N-containingheterocyclyl-C₁-C₄-alkylamino, C₁-C₄-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkylamino-C₁-C₄-alkyl, andC₁-C₄-alkylamino-C₁-C₄-alkylamino; wherein R¹⁶ is selected from H,heterocyclylcarbonyl, alkylaminocarbonyl, alkylaminomethyl, andheterocyclylmethyl; and wherein R¹⁷ is selected from halo, C₁-C₆-alkyl,cycloalkylalkynyl, cycloalkyl, optionally substituted indolyl,optionally substituted indazolyl, optionally substituted phenoxy,optionally substituted heteroarylsulfonyl-C₁-C₄-alkyl, unsubstituted5-membered oxygen or sulfur containing heteroaryl, unsubstituted6-membered nitrogen-containing heterocyclyl, phenyl optionallysubstituted with one or two substituents selected from halo,C₁-C₄-alkylamino, amino, nitro, C₁-C₄-alkoxy, C₁-C₂-haloalkyl, hydroxy,C₁-C₄-alkylthio, C₁-C₄-alkylcarbonylamino, (optionally substitutedphenyl)sulfonylamino, cyano, C₁-C₂-haloalkoxy, 5- or 6-memberedN-containing heterocyclyl, aminosulfonyl, (6-membered N-containingheterocyclyl)sulfonyl, C₁-C₂-haloalkylcarbonylaminosulfonyl and(optionally substituted phenyl)aminosulfonyl, and 6-memberednitrogen-containing heterocyclyl substituted with one or moresubstituents independently selected from pyridyl, phenyl, C₁-C₄ alkyl,C₁-C₂ haloalkyl, C₁-C₂ alkoxy, amino, halo, piperidinyl, morpholinyl,C₁-C₂ alkylpiperazinyl, C₁-C₃ alkylaminothiocarbonyl,N,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenyl,N—C₁-C₂-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,C₁-C₂-haloalkylcarbonylamino, morpholinyl-C₁-C₄-alkylenylamino,N,N-di-C₁-C₂-alkylamino andN,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenylamino; and pharmaceuticallyacceptable derivatives thereof; provided only one of R¹⁵ and R¹⁶ is H.2. A compound of claim 1 wherein R¹⁵ is selected from H, optionallysubstituted pyrrolidinyl, optionally substituted piperazinyl, optionallysubstituted piperidinyl, morpholinyl, 1,2,3,6-tetrahydro-pyridinyl,(optionally substituted pyrrolidinyl)-C₁-C₂-alkyl, (optionallysubstituted piperidinyl) -C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, morpholinyl-C₁-C₂-alkyl,C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-hydroxyalkylamino, (optionallysubstituted pyrrolidinyl) -C₁-C₂-alkylamino, (optionally substitutedpiperidinyl) -C₁-C₂-alkylamino, (optionally substituted piperazinyl)-C₁-C₂-alkylamino, morpholinyl-C₁-C₂-alkylamino, optionally substitutedpyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, tetrahydrofuryl-C₁-C₄-alkoxy, optionallysubstituted piperidinyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy,tetrahydrofuryloxy, optionally substituted piperidinyloxy, optionallysubstituted phenoxy, C₁-C₄-alkylaminocarbonyl andC₁-C₄-alkylaminothiocarbonyl; wherein R¹⁶ is selected from H,5-6-membered nitrogen containing heterocyclylcarbonyl,C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkylaminomethyl, and 5-6-memberednitrogen containing heterocyclylmethyl; and wherein R¹⁷ is selected fromhalo, C₁-C₂-alkyl, optionally substituted 5-6-memberedheteroarylsulfonyl-C₁-C₂-alkyl, optionally substituted phenoxy, andC₃-C₆-cycloalkyl-C₂-C₄-alkynyl; and pharmaceutically acceptablederivatives thereof.
 3. A compound of claim 2 wherein R¹⁵ is selectedfrom H, tetrahydro-furanyloxy, 1-methylpyrrolidin-2-ylmethoxy,2-pyrrolidinylmethoxy, 3-pyrrolidinylmethoxy,1-Boc-pyrrolidin-2-ylmethoxy, 4-piperidinylmethoxy,1-Boc-piperidin-4-ylmethoxy, 1-Boc-piperidin-4-ylethoxy,piperidin-4-ylethoxy, 1-methyl-piperidin-4-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, 1-methyl-azetidin-3-ylmethoxy,3-azetidinylmethoxy, 1-methyl-piperidin-4-yloxy, phenyloxy,4-(pyrrolidin-1-ylmethyl)phenoxy, dimethylaminoethoxy,1-piperidinylmethyl, 1-(piperidin-1-yl)ethyl,3-methylpiperidin-1-ylmethyl, 1-pyrrolidinylmethyl,2,2,6,6-tetramethylpiperidin-1-ylmethyl,2,6-dimethylpiperidin-1-ylmethyl, dimethylaminomethyl,diethylaminomethyl, diethylaminothiocarbonyl, diethylaminocarbonyl,N-Boc-N-isopropylaminomethyl, isopropylaminomethyl,2-thienylsulfonylmethyl, hydroxypropylamino, 4-ethyl-piperidin-1-yl,4-(2-pyridyl)piperidin-1-yl, 1-methylpiperidin-4-yl,4-(2-pyrazinyl)piperidin-1-yl, 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl,1,2,3,6-tetrahydro-pyridin-4-yl, and1-Boc-1,2,3,6-tetrahydro-pyridin-4-yl; wherein R¹⁶ is selected from H,1-piperidinylcarbonyl, diethylaminocarbonyl, diethylaminomethyl,1-piperidinylmethyl; and wherein R¹⁷ is selected from chloro, bromo,methyl and cyclopropylethynyl; and pharmaceutically acceptablederivatives thereof.
 4. A compound of claim 3 wherein R¹⁷ is chloro orbromo; and pharmaceutically acceptable derivatives thereof.
 5. Acompound of claim 1 wherein R¹⁵ is selected from H, optionallysubstituted pyrrolidinyl, optionally substituted piperazinyl, optionallysubstituted piperidinyl, morpholinyl, 1,2,3,6-tetrahydro-pyridinyl,(optionally substituted pyrrolidinyl)-C₁-C₂-alkyl, (optionallysubstituted piperidinyl)-C₁-C₂-alkyl, (optionally substitutedpiperazinyl)-C₁-C₂-alkyl, morpholinyl-C₁-C₂-alkyl, (optionallysubstituted pyrrolidinyl)-C₁-C₂-alkylamino, (optionally substitutedpiperidinyl)-C₁-C₂-alkylamino, (optionally substitutedpiperazinyl)-C₁-C₂-alkylamino, morpholinyl-C₁-C₂-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-hydroxyalkylamino, optionallysubstituted pyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, tetrahydrofuryl-C₁-C₄-alkoxy, optionallysubstituted piperidinyl-C₁-C₄-alkoxy, C₁-C₄-alkylamino-C₁-C₄-alkoxy,tetrahydrofuryloxy, optionally substituted piperidinyloxy, optionallysubstituted phenoxy, C₁-C₄-alkylaminocarbonyl andC₁-C₄-alkylaminothiocarbonyl; wherein R¹⁶ is selected from H,5-6-membered nitrogen containing heterocyclylcarbonyl,C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkylaminomethyl, and 5-6-memberednitrogen containing heterocyclylmethyl; and wherein R¹⁷ is selected fromC₃-C₆-cycloalkyl and phenyl optionally substituted with one or twosubstituents selected from halo, C₁-C₄-alkylamino, amino, nitro,C₁-C₄-alkoxy, C₁-C₂-haloalkyl, hydroxy, C₁-C₄-alkylthio,C₁-C₄-alkylcarbonylamino, (optionally substituted phenyl)sulfonylamino,cyano, C₁-C₂-haloalkoxy, 5- or 6-membered N-containing heterocyclyl,aminosulfonyl, (6-membered N-containing heterocyclyl)sulfonyl,C₁-C₂-haloalkylcarbonylaminosulfonyl and (optionally substitutedphenyl)aminosulfonyl; and pharmaceutically acceptable derivativesthereof.
 6. A compound of claim 5 wherein R¹⁵ is selected from H,tetrahydro-furanyloxy, 1-methylpyrrolidin-2-ylmethoxy,2-pyrrolidinylmethoxy, 3-pyrrolidinylmethoxy,1-Boc-pyrrolidin-2-ylmethoxy, 4-piperidinylmethoxy,1-Boc-piperidin-4-ylmethoxy, 1-Boc-piperidin-4-ylethoxy,piperidin-4-ylethoxy, 1-methyl-piperidin-4-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, 1-methyl-azetidin-3-ylmethoxy,3-azetidinylmethoxy, 1-methyl-piperidin-4-yloxy, phenyloxy,4-(pyrrolidin-1-ylmethyl)phenoxy, dimethylaminoethoxy,1-piperidinylmethyl, 1-(piperidin-1-yl)ethyl,3-methylpiperidin-1-ylmethyl, 1-pyrrolidinylmethyl,2,2,6,6-tetramethylpiperidin-1-ylmethyl,2,6-dimethylpiperidin-1-ylmethyl, dimethylaminomethyl,diethylaminomethyl, diethylaminothiocarbonyl, diethylaminocarbonyl,N-Boc-N-isopropylaminomethyl, isopropylaminomethyl,2-thienylsulfonylmethyl, hydroxypropylamino, 4-ethyl-piperidin-1-yl,4-(2-pyridyl)piperidin-1-yl, 1-methylpiperidin-4-yl,4-(2-pyrazinyl)piperidin-1-yl, 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl,1,2,3,6-tetrahydro-pyridin-4-yl, and1-Boc-1,2,3,6-tetrahydro-pyridin-4-yl; wherein R¹⁶ is selected from H,1-piperidinylcarbonyl, diethylaminocarbonyl, diethylaminomethyl,1-piperidinylmethyl; and wherein R¹⁷ is selected from cyclopropyl andphenyl optionally substituted with aminosulfonyl; and pharmaceuticallyacceptable derivatives thereof.
 7. A compound of claim 6 wherein R¹⁷ isunsubstituted phenyl; and pharmaceutically acceptable derivativesthereof.
 8. Compound of claim 1 wherein R¹⁵ is selected from H,optionally substituted pyrrolidinyl, optionally substituted piperazinyl,optionally substituted piperidinyl, morpholinyl,1,2,3,6-tetrahydro-pyridinyl, (optionally substitutedpyrrolidinyl)-C₁-C₂-alkyl, (optionally substituted piperidinyl)-C₁-C₂-alkyl, (optionally substituted piperazinyl) -C₁-C₂-alkyl,morpholinyl-C₁-C₂-alkyl, (optionally substituted pyrrolidinyl)-C₁-C₂-alkylamino, (optionally substitutedpiperidinyl)-C₁-C₂-alkylamino, (optionally substituted piperazinyl)-C₁-C₂-alkylamino, morpholinyl-C₁-C₂-alkylamino,C₁-C₄-alkylamino-C₁-C₄-alkyl, C₁-C₄-hydroxyalkylamino, optionallysubstituted pyrrolidinyl-C₁-C₄-alkoxy, optionally substitutedazetidinyl-C₁-C₄-alkoxy, tetrahydrofuryl-C₁-C₄-alkoxy, optionallysubstituted piperidinyl-C₁-C₄-alkoxy, C₁-C₄alkylamino-C₁-C₄-alkoxy,tetrahydrofuryloxy, optionally substituted piperidinyloxy, optionallysubstituted phenoxy, C₁-C₄-alkylaminocarbonyl andC₁-C₄-alkylaminothiocarbonyl; wherein R¹⁶ is selected from H,5-6-membered nitrogen containing heterocyclylcarbonyl,C₁-C₄-alkylaminocarbonyl, C₁-C₄-alkylaminomethyl, and 5-6-memberednitrogen containing heterocyclylmethyl; and wherein R¹⁷ is selected fromoptionally substituted indazolyl, optionally substituted indolyl,unsubstituted 5-membered oxygen or sulfur containing heteroaryl,unsubstituted 6-membered nitrogen-containing heterocyclyl, and6-membered nitrogen-containing heterocyclyl substituted with one or moresubstituents independently selected from pyridyl, phenyl, C₁-C₄ alkyl,C₁-C₂ haloalkyl, C₁-C₂ alkoxy, amino, halo, piperidinyl, morpholinyl,C₁-C₂ alkylpiperazinyl, C₁-C₃ alkylaminothiocarbonyl,N,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenyl,N—C₁-C₂-alkylamino-C₁-C₄-alkylenyl,morpholinyl-C₁-C₄-alkylenylaminocarbonyl, aminocarbonyl,C₁-C₂-haloalkylcarbonylamino, morpholinyl-C₁-C₄-alkylenylamino,N,N-di-C₁-C₂-alkylamino andN,N-di-C₁-C₂-alkylamino-C₁-C₄-alkylenylamino; and pharmaceuticallyacceptable derivatives thereof.
 9. Compound of claim 8 wherein R¹⁵ isselected from H, tetrahydro-furanyloxy, 1-methylpyrrolidin-2-ylmethoxy,2-pyrrolidinylmethoxy, 3-pyrrolidinylmethoxy,1-Boc-pyrrolidin-2-ylmethoxy, 4-piperidinylmethoxy,1-Boc-piperidin-4-ylmethoxy, 1-Boc-piperidin-4-ylethoxy,piperidin-4-ylethoxy, 1-methyl-piperidin-4-ylmethoxy,1-Boc-azetidin-3-ylmethoxy, 1-methyl-azetidin-3-ylmethoxy,3-azetidinylmethoxy, 1-methyl-piperidin-4-yloxy, phenyloxy,4-(pyrrolidin-1-ylmethyl)phenoxy, dimethylaminoethoxy,1-piperidinylmethyl, 1-(piperidin-1-yl)ethyl,3-methylpiperidin-1-ylmethyl, 1-pyrrolidinylmethyl,2,2,6,6-tetramethylpiperidin-1-ylmethyl,2,6-dimethylpiperidin-1-ylmethyl, dimethylaminomethyl,diethylaminomethyl, diethylaminothiocarbonyl, diethylaminocarbonyl,N-Boc-N-isopropylaminomethyl, isopropylaminomethyl,2-thienylsulfonylmethyl, hydroxypropylamino, 4-ethyl-piperidin-1-yl,4-(2-pyridyl)piperidin-1-yl, 1-methylpiperidin-4-yl,4-(2-pyrazinyl)piperidin-1-yl, 1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl,1,2,3,6-tetrahydro-pyridin-4-yl, and1-Boc-1,2,3,6-tetrahydro-pyridin-4-yl; wherein R¹⁶ is selected from H,1-piperidinylcarbonyl, diethylaminocarbonyl, diethylaminomethyl,1-piperidinylmethyl; and wherein R¹⁷ is selected from 5-indazolyl,1-Boc-indol-5-yl, unsubstituted thienyl, 5-tert-butyloxazol-2-yl and4-pyridyl substituted with one or more substituents independentlyselected from methoxy and chloro; and pharmaceutically acceptablederivatives thereof.
 10. A compound of claim 9 wherein R¹⁷ is 4-pyridyl;and pharmaceutically acceptable derivatives thereof.
 11. Compound ofclaim 1 and pharmaceutically acceptable derivatives thereof selectedfrom:1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-[4-(Piperidine-1-carbonyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-(2-Chloro-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;N,N-Diethyl-2-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-isonicotinamide;N,N-Diethyl-2-[3-(2-phenyl-thiazol-4-yl)-ureido]-isonicotinamide;2-[3-(2-Bromo-thiazol-4-yl)-ureido]-N,N-diethyl-isonicotinamide;1-(4-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Piperidin-1-yl-ethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;1-{6-[(Piperidin-2-ylmethyl)-amino]-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;(S)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;(R)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2pyridin-4-yl-thiazol-4-yl)-urea;1-(2-Chloro-thiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-bromo-thiazol-4-yl)-urea;1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-chloro-thiazol-4-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)pyridin-2-yl]-urea;tert-Butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl}-pyrrolidine-1-carboxylate;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-3-ylmethoxy)-pyridin-2-yl]-urea;1-(2-Cyclopropyl-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6-(isopropylamino-methyl)-pyridin-2-yl]-urea;1-(2-Bromo-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;1-(2-phenylthiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-urea;1-[2-(1H-Indazol-5-yl)-thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4yl)-urea;1-(2-Bromo-thizol-4-yl)-3-(1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea;1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-2[2,4]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea;1-[6-(3-Hydroxy-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thizol-4-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6(3-hydroxy-propylamino)-pyridin-2-yl]-urea;1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipydrinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea;6-[3-(2-Pyridin-4-yl-thizol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylicacid tert-butylester;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea;1-(2-Pyridin-4-yl-thizol-4-yl)-3-[6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-yl]-urea;2-[6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridine-2-carbothioic aciddiethylamide;1-(2-Bromo-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;1-(2-Phenyl-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;1-(2-Bromo-thiazol-4-yl)-3-[4-(piperidine-1-carbonyl)-pyridin-2-yl]-urea;1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-phenoxy-pyridin-2-yl)-urea;1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;1-[6-(2-Dimethylamino-ethoxy)-pyridin-2-yl]-3-[2-(2-methoxy-pyridin-4-yl)-thiazol-4-yl]-urea;1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-(2-phenylthiazol-4-yl)-3-(6-pyrrolidin-1-ylmethyl-pyridin-2-yl)urea;1-(6-Diethylaminomethylpyridin-2-yl)-3-(2-phenylthiazol-4-yl)urea;(S)-1-[6-(1-Methylpyrrolidin-2-ylmethoxy)pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea;1-[6-(2-Piperidin-4-yl-ethoxy)pyridin-2-yl]-3-[2-phenylthiazol-4-yl]urea;1-[6-(4-Ethylpiperazin-1-yl)-pyridin-2-yl]-3-(2phenylthiazol-4-yl)urea;Diethyl 6-[3-(2-phenylthiazol-4-yl)ureido]-pyridine-2-carboxamide;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;1-(2-Bromothiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;1-[6-(Piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-(2-Phenyl-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-[6-(2-Piperidin-4-yl-ethoxy)-pyridin-2-yl]-3-(2-thiophen-2-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-[2-(thiophene-2-sulfonylmethyl)-thiazol-4-yl]-urea;1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea;and[2-(2-Chloro-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea.12. Compound of claim 1 and pharmaceutically acceptable derivativesthereof selected from:1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-[4-(Piperidine-1-carbonyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;N,N-Diethyl-2-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-isonicotinamide;1-(4-Diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(2,6-Dimethyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Piperidin-1-yl-ethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;2-({6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylamino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;1-{6-[(Piperidin-2-ylmethyl)-amino]-pyridin-2-yl}-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;(S)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;(R)-1-[6-(3-Methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-(2-Chloro-thiazol-4-yl)-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-bromo-thiazol-4-yl)-urea;1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-chloro-thiazol-4-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)-pyridin-2-yl]-urea;3-(4-{3-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-ureido)-thiazol-2-yl)-benzenesulfonamide;tert-Butyl3-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl)-pyrrolidine-1-carboxylate;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-3-ylmethoxy)-pyridin-2-yl]-urea;1-(2-Cyclopropyl-thiazol-4-yl)-3-[6-(2-piperidin-4-yl-ethoxy)-pyridin-2-yl]-urea;Isopropyl-{6-[3-(2-pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl)-carbamicacid tert-butyl ester;1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;Isopropyl-{6-[3-(2-phenyl-thiazol-4-yl)-ureido]-pyridin-2-ylmethyl)-carbamicacid tert-butyl ester;1-[6-(Isopropylamino-methyl)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;1-(2-phenylthiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(tetrahydro-furan-3-yloxy)-pyridin-2-yl]-urea;1-[2-(1H-Indazol-5-yl)-thiazol-4-yl]-3-(6-piperidin-1-ylmethyl-pyridin-2-yl)-urea;1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4yl)-urea;1-(2-Bromo-thizol-4-yl)-3-(1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea;1-(1′-Methyl-1′,2′,3′,6′-tetrahydro-2[2,4]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea;1-[6-(3-Hydroxy-propylamino)-pyridin-2-yl]-3-(2-pyridin-4-yl-thizol-4-yl)-urea;1-(2-Bromo-thiazol-4-yl)-3-[6(3-hydroxy-propylamino)-pyridin-2-yl]-urea;1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipydrinyl-6-yl)-3-(2-pyridin-4-yl-thiazol-4yl)-urea;1-(1′-Methyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-6-yl)-3-(2-phenyl-thiazol-4-yl)-urea;6-[3-(2-Pyridin-4-yl-thizol-4-yl)-ureido]-3′,6′-dihydro-2′H-[2,4]bipyridinyl-1′-carboxylicacid tert-butylester;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-yl)-urea;1-(2-Pyridin-4-yl-thizol-4-yl)-3-[6-(tetrahydro-furan-3-ylmethoxy)-pyridin-2-yl]-urea;2-[6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridin-2-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-[6-(pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;6-[3-(2-Pyridin-4-yl-thiazol-4-yl)-ureido]-pyridine-2-carbothioic aciddiethylamide;1-(2-Bromo-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;1-(2-Chloro-thiazol-4-yl)-3-[6-(3-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-urea;1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-[6-(1-methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-urea;1-[6-(2-Dimethylamino-ethoxy)-pyridin-2-yl]-3-[2-(2-methoxy-pyridin-4-yl)-thiazol-4-yl]-urea;1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-(2-phenylthiazol-4-yl)-3-(6-pyrrolidin-1-ylmethyl-pyridin-2-yl)urea;1-(6-Diethylaminomethylpyridin-2-yl)-3-(2-phenylthiazol-4yl)urea;(S)-1-[6-(1-Methylpyrrolidin-2-ylmethoxy)pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea;1-[6-(2-Piperidin-4-yl-ethoxy)pyridin-2-yl]-3-[2-phenylthiazol-4-yl]urea;1-[6-(4-Ethylpiperazin-1-yl)-pyridin-2-yl]-3-(2-phenylthiazol-4-yl)urea;1-(2-phenylthiazol-4-yl)-3-[6-(4-pyrimidin-2-yl-piperazin-1-yl)pyridin-2-yl]urea;Diethyl 6-[3-(2-phenylthiazol-4-yl)ureido]-pyridine-2-carboxamide;1-(2-Pyridin-4-yl-thiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;1-(2-Bromothiazol-4-yl)-3-(6-p-pyrrolidin-1-ylmethylphenoxypyridin-2-yl)urea;1-[6-(Piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2pyridin-4-yl-thiazol-4-yl)-urea;1-[6-(Azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-[6-(1-Methyl-azetidin-3-ylmethoxy)-pyridin-2-yl]-3-(2-phenyl-thiazol-4-yl)-urea;1-(2-Phenyl-thiazol-4-yl)-3-[6-(piperidin-4-ylmethoxy)pyridin-2-yl]-urea;1-[6-(1-Methyl-piperidin-4-ylmethoxy)-pyridin-2-yl]-3-(2phenyl-thiazol-4-yl)-urea;1-[6-(1-Methyl-piperidin-4-yloxy)-pyridin-2-yl]-3-(2-phenylthiazol-4-yl)-urea;1-[6-(2-Piperidin-4-yl-ethoxy)-pyridin-2-yl]-3-(2-thiophen-2-yl-thiazol-4-yl)-urea;1-[6-(1-Methyl-pyrrolidin-2-ylmethoxy)-pyridin-2-yl]-3-[2-(thiophene-2-sulfonylmethyl)-thiazol-4-yl]-urea;1-[2-(2-Methoxy-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea;and[2-(2-Chloro-pyridin-4-yl)-thiazol-4-yl]-3-(6-piperdin-1-ylmethyl-pyridin-2-yl)-urea.13. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a compound of claim
 1. 14. A method of inhibitingcell proliferation which comprises administering an effective amount ofa compound of claim
 1. 15. A method of treating cancer which comprisesadministering an effective amount of a compound of claim
 1. 16. A methodof inhibiting a serine/threonine kinase which comprises administering aneffective amount of a compound of claim
 1. 17. A method of treating aneurological disorder which comprises administering an effective amountof a compound of claim 1.